前田 法一 (マエダ ノリカズ)

  • 医学科 教授/主任
Last Updated :2024/04/23

コミュニケーション情報 byコメンテータガイド

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    糖尿病(特に肥満2型糖尿病)、メタボリックシンドローム、脂質異常症、高血圧症、動脈硬化症などの生活習慣病
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研究者情報

学位

  • 博士(医学)(2003年03月 大阪大学)
  • 学士(医学)(1995年03月 大阪大学)

ホームページURL

J-Global ID

研究キーワード

  • Metabolic syndrome   糖尿病   動脈硬化   メタボリックシンドローム   

現在の研究分野(キーワード)

    糖尿病(特に肥満2型糖尿病)、メタボリックシンドローム、脂質異常症、高血圧症、動脈硬化症などの生活習慣病

研究分野

  • ライフサイエンス / 代謝、内分泌学

経歴

  • 2023年04月 - 現在  近畿大学医学部 医学科主任教授

学歴

  •         - 2003年   大阪大学大学院   医学系研究科   生体制御医学専攻、分子制御内科学
  •         - 2003年   大阪大学   Graduate School of Medicine   Internal Medicine and Molecular Science
  •         - 1995年   大阪大学   医学部   医学科
  •         - 1995年   大阪大学   Faculty of Medicine

所属学協会

  • 日本内分泌学会   日本糖尿病学会   日本肥満学会   日本内科学会   日本動脈硬化学会   

研究活動情報

論文

  • Naru Babaya; Shinsuke Noso; Yoshihisa Hiromine; Yasunori Taketomo; Fumimaru Niwano; Sawa Yoshida; Sara Yasutake; Yumiko Kawabata; Norikazu Maeda; Hiroshi Ikegami
    Scientific Reports 14 1 1 - 8 2024年03月 [査読有り]
     
    Abstract Continuous glucose monitoring (CGM) values obtained from CGM systems using the same sensor but with different internal algorithms (the first- and third-generation FreeStyle Libre (1st-gen-libre and 3rd-gen-libre, respectively)) were compared. We used 19,819 paired and simultaneously measured CGM values of 13 patients with diabetes. The average CGM value was significantly higher (P < 0.0001) and the time below range (CGM value < 70 mg/dL) was significantly lower (P < 0.0001) with the 3rd-gen-libre than with the 1st-gen-libre. There was a significant correlation (P < 0.0001) between the CGM values of the 3rd-gen-libre (y-axis, mg/dL) and 1st-gen-libre (x-axis, mg/dL) using the following formula: y = 0.9728x + 10.024. On assessing the association between glycated hemoglobin (HbA1c (%), y-axis) and the average CGM values (x-axis, mg/dL) by applying the obtained equation to previously reported 1st-gen-libre data and converting it to 3rd-gen-libre data, we obtained the equation y = 0.02628x + 3.233, indicating that the glucose management indicator reported in the West may be underestimated compared with the laboratory-measured HbA1c in the Japanese population. Glucose values from the same sensor were found to be significantly different between readers with different algorithms, and the calculation of CGM-related indices may need to be individualized for each device.
  • Shuzo Imamura; Fumimaru Niwano; Naru Babaya; Yoshihisa Hiromine; Ippei Matsumoto; Keiko Kamei; Yuta Yoshida; Yasunori Taketomo; Sawa Yoshida; Yoshifumi Takeyama; Shinsuke Noso; Norikazu Maeda; Hiroshi Ikegami
    The Journal of Clinical Endocrinology & Metabolism 109 3 619 - 630 2024年03月 [査読有り]
     
    Abstract Context Glucose tolerance worsens after distal pancreatectomy (DP); however, the long-term incidence and factors affecting interindividual variation in this worsening are unclear. Objective To investigate the changes in diabetes-related traits before and after DP and to clarify the incidence of diabetes and its predictors. Methods Among 493 registered patients, 117 underwent DP. Among these, 56 patients without diabetes before surgery were included in the study. Glucose and endocrine function were prospectively assessed using a 75-g oral glucose tolerance test preoperatively, 1 month after DP, and every 6 months thereafter for up to 36 months. Pancreatic volumetry was performed using multidetector row computed tomography before and after surgery. Results Insulin secretion decreased and blood glucose levels worsened after DP. Residual pancreatic volume was significantly associated with the reserve capacity of insulin secretion but not with blood glucose levels or the development of diabetes. Among 56 patients, 33 developed diabetes mellitus. The cumulative incidence of diabetes at 36 months after DP was 74.1%. Multivariate Cox regression analysis showed that impaired glucose tolerance as a preoperative factor as well as a decreased insulinogenic index and impaired glucose tolerance at 1 month postoperatively were identified as risk factors for diabetes following DP. Conclusion Impaired glucose tolerance and reduced early-phase insulin response to glucose are involved in the development of new-onset diabetes after DP; the latter is an additional factor in the development of diabetes and becomes apparent when pancreatic beta cell mass is reduced after DP.
  • Kohei Fujii; Yuya Fujishima; Shunbun Kita; Keitaro Kawada; Keita Fukuoka; Taka-aki Sakaue; Tomonori Okita; Emi Kawada-Horitani; Hirofumi Nagao; Shiro Fukuda; Norikazu Maeda; Hitoshi Nishizawa; Iichiro Shimomura
    Scientific Reports 14 1 1 - 12 2024年02月 [査読有り]
     
    Abstract Pharmacological activation of hypoxia-inducible factor 1 (HIF-1), a hypoxia-responsive transcription factor, has attracted increasing attention due to its efficacy not only in renal anemia but also in various disease models. Our study demonstrated that a HIF-1 activator enhanced extracellular vesicle (EV) production from cultured endothelial cells synergistically with adiponectin, an adipocyte-derived factor, through both transcriptional induction and posttranscriptional stabilization of an adiponectin binding partner, T-cadherin. Increased EV levels were observed in wild-type mice but not in T-cadherin null mice after consecutive administration of roxadustat. Adiponectin- and T-cadherin-dependent increased EV production may be involved in the pleiotropic effects of HIF-1 activators.
  • Hirofumi Nagao; Hitoshi Nishizawa; Shiro Fukuda; Yuya Fujishima; Shunbun Kita; Norikazu Maeda; Takeshi Bamba; Eiichiro Fukusaki; Iichiro Shimomura
    Endocrine Journal 71 1 55 - 63 2024年01月
  • Keita Fukuoka; Ryohei Mineo; Shunbun Kita; Shiro Fukuda; Tomonori Okita; Emi Kawada-Horitani; Masahito Iioka; Kohei Fujii; Keitaro Kawada; Yuya Fujishima; Hitoshi Nishizawa; Norikazu Maeda; Iichiro Shimomura
    Journal of Biological Chemistry 299 9 105114 - 105114 2023年09月 [査読有り]
  • Yuya Fujishima; Shunbun Kita; Hitoshi Nishizawa; Norikazu Maeda; Iichiro Shimomura
    Endocrine Journal 70 7 663 - 675 2023年07月 [査読有り]
  • 糖尿病・メタボリックシンドロームと動脈硬化 メタボリックシンドロームにおける血管障害・動脈硬化症の進展に関わる分子メカニズム
    藤島 裕也; 喜多 俊文; 西澤 均; 前田 法一; 下村 伊一郎
    日本動脈硬化学会総会プログラム・抄録集 55回 144 - 144 (一社)日本動脈硬化学会 2023年06月
  • Keitaro Kawada; Shunbun Kita; Shiro Fukuda; Keita Fukuoka; Tomonori Okita; Emi Kawada-Horitani; Masahito Iioka; Taka-aki Sakaue; Yusuke Kawachi; Kohei Fujii; Yu Kimura; Shuichi Otabe; Yuya Fujishima; Hitoshi Nishizawa; Norikazu Maeda; Iichiro Shimomura
    Endocrine Journal 70 6 635 - 645 2023年06月 [査読有り]
  • 減量・代謝改善手術による食行動の変化と術後1年の体重減少との関連性
    木村 優; 藤島 裕也; 徳澤 千恵; 西澤 均; 白波瀬 景子; 竹治 香菜; 山口 智勢; 長井 直子; 川知 祐介; 福田 士郎; 喜多 俊文; 西塔 拓郎; 宮崎 安弘; 前田 和久; 前田 法一; 土岐 祐一郎; 下村 伊一郎
    日本内分泌学会雑誌 99 1 296 - 296 (一社)日本内分泌学会 2023年05月
  • 馬殿 恵; 加藤 更紗; 仁木 暁子; 満塩 研人; 原 知之; 木村 優; 川知 祐介; 小澤 栄稔; 石橋 千咲; 細川 吉弥; 藤田 有可里; 藤島 裕也; 徳永 あゆみ; 南茂 隆生; 小澤 純二; 西澤 均; 前田 法一; 下村 伊一郎
    日本内分泌学会雑誌 99 1 212 - 212 (一社)日本内分泌学会 2023年05月
  • Lixin Fang; Koji Ohashi; Satoko Hayakawa; Hayato Ogawa; Naoya Otaka; Hiroshi Kawanishi; Tomonobu Takikawa; Yuta Ozaki; Kunihiko Takahara; Minako Tatsumi; Mikito Takefuji; Yuuki Shimizu; Yasuko K. Bando; Yuya Fujishima; Norikazu Maeda; Iichiro Shimomura; Toyoaki Murohara; Noriyuki Ouchi
    iScience 26 5 106591 - 106591 2023年05月 [査読有り]
  • 調理指導を含めた生活習慣改善プログラムの開発 中間報告(第二報)
    馬殿 恵; 加藤 更紗; 仁木 暁子; 満塩 研人; 原 知之; 木村 優; 川知 祐介; 小澤 栄稔; 石橋 千咲; 細川 吉弥; 藤田 有可里; 藤島 裕也; 徳永 あゆみ; 南茂 隆生; 小澤 純二; 西澤 均; 前田 法一; 下村 伊一郎
    糖尿病 66 Suppl.1 S - 241 (一社)日本糖尿病学会 2023年04月
  • Risa Kashiwagi-Takayama; Junji Kozawa; Yoshiya Hosokawa; Sarasa Kato; Satoshi Kawata; Harutoshi Ozawa; Ryohei Mineo; Chisaki Ishibashi; Megu Y Baden; Ryuya Iwamoto; Kenji Saisho; Yukari Fujita; Sachiko Tamba; Takuya Sugiyama; Hitoshi Nishizawa; Norikazu Maeda; Koji Yamamoto; Masahiro Higashi; Yuya Yamada; Yasushi Sakata; Yuji Matsuzawa; Iichiro Shimomura
    Cardiovascular diabetology 22 1 48 - 48 2023年03月 [査読有り]
     
    BACKGROUND: Ectopic fat is fat that accumulates in or around specific organs or compartments of the body including myocardium. The clinical features of type 2 diabetes patients with high fat accumulation in the myocardium remain unknown. Moreover, little is known about the influence of myocardial fat accumulation in type 2 diabetes on coronary artery disease and cardiac dysfunction. We aimed to clarify the clinical features, including cardiac functions, of type 2 diabetes patients with myocardial fat accumulation. METHODS: We retrospectively enrolled type 2 diabetes patients who underwent ECG-gated coronary computed tomography angiography (CCTA) and abdominal computed tomography (CT) scan examinations within 1 year of CCTA from January 2000 to March 2021. High fat accumulation in the myocardium was defined as the low mean myocardial CT value of three regions of interest, and the associations between CT values and clinical characteristics or cardiac functions were assessed. RESULTS: In total, 124 patients were enrolled (72 males and 52 females). The mean age was 66.6 years, the mean BMI was 26.2 kg/m2, the mean ejection fraction (EF) was 67.6%, and the mean myocardial CT value was 47.7 Hounsfield unit. A significant positive correlation was found between myocardial CT value and EF (r = 0.3644, p = 0.0004). The multiple regression analyses also showed that myocardial CT value was independently associated with EF (estimate, 0.304; 95% confidence interval (CI) 0.092 to 0.517; p = 0.0056). Myocardial CT value showed significant negative correlations with BMI, visceral fat area and subcutaneous fat area (r = - 0.1923, - 0.2654, and -0.3569, respectively, p < 0.05). In patients who were ≥ 65 years or female, myocardial CT value showed significant positive correlations with not only EF (r = 0.3542 and 0.4085, respectively, p < 0.01) but also early lateral annular tissue Doppler velocity (Lat e') (r = 0.5148 and 0.5361, respectively, p < 0.05). The multiple regression analyses showed that myocardial CT value was independently associated with EF and Lat e' in these subgroups (p < 0.05). CONCLUSIONS: Patients with type 2 diabetes, especially in elderly or female patients, who had more myocardial fat had more severe left ventricular systolic and diastolic dysfunctions. Reducing myocardial fat accumulation may be a therapeutic target for type 2 diabetes patients.
  • Yuya Fujishima; Hitoshi Nishizawa; Yusuke Kawachi; Takashi Nakamura; Seigo Akari; Yoshiyuki Ono; Shiro Fukuda; Shunbun Kita; Norikazu Maeda; Satoshi Hoshide; Iichiro Shimomura; Kazuomi Kario
    Biomedicines 11 3 674 - 674 2023年02月 [査読有り]
     
    Background: The effects of uric acid (UA)-lowering therapy with xanthine oxidoreductase (XOR) inhibitors on the development of cardiovascular diseases remain controversial. Based on recent findings that plasma XOR activity increased in liver disease conditions, we conducted a sub-analysis of the BEYOND-UA study to examine the differential effects of topiroxostat on arterial stiffness based on liver function in hyperuricemic individuals with hypertension. Methods: Sixty-three subjects treated with topiroxostat were grouped according to baseline alanine aminotransferase (ALT) levels (above or below cut-off values of 22, 30, or 40 U/L). The primary endpoint was changes in the cardio-ankle vascular index (CAVI) from baseline to 24 weeks. Results: Significant reductions in CAVI during topiroxostat therapy occurred in subjects with baseline ALT ≥30 U/L or ≥40 U/L, and significant between-group differences were detected. Brachial-ankle pulse wave velocity significantly decreased in the ALT-high groups at all cut-off values. Reductions in morning home blood pressure and serum UA were similar regardless of the baseline ALT level. For eleven subjects with available data, ALT-high groups showed high plasma XOR activity, which was significantly suppressed by topiroxostat. Conclusions: Topiroxostat improved arterial stiffness parameters in hyperuricemic patients with liver dysfunction, which might be related to its inhibitory effect on plasma XOR.
  • Yu Kimura; Yuya Fujishima; Hitoshi Nishizawa; Takuro Saito; Yasuhiro Miyazaki; Keiko Shirahase; Chie Tokuzawa; Naoko Nagai; Shiro Fukuda; Kazuhisa Maeda; Norikazu Maeda; Yuichiro Doki; Iichiro Shimomura
    Nutrients 15 2 353 - 353 2023年01月 [査読有り]
     
    Background: Metabolic and bariatric surgery (MBS) has been established to provide long-term weight loss in severe obesity. In this study, we investigated the factors that affect post-operative weight loss, with a particular focus on changes in eating behaviors. Methods: Time-course changes in body weight and eating behaviors were examined in 49 Japanese patients who underwent laparoscopic sleeve gastrectomy from the first visit to 12 months after surgery. Each eating behavior was evaluated via the questionnaire of the Japan Society for the Study of Obesity. Results: Pre-operative weight reduction mediated by dietary and lifestyle interventions showed significant positive correlations with weight loss outcomes at 12 months after surgery. We observed significant decreases in scores for most of the eating behaviors 12 months after surgery. However, “emotional eating behavior” scores declined temporarily in the early post-operative period of one month but thereafter returned to the pre-operative level at 12 months. Furthermore, increases in the scores for “emotional eating behavior” and “sense of hunger” from 1 to 12 months post-operatively were significantly associated with poor weight loss. Conclusions: Our results demonstrate the beneficial effects of MBS on obesity-related eating behaviors, as well as highlighting “emotional eating behavior” as requiring particular attention.
  • Masahito Iioka; Shiro Fukuda; Norikazu Maeda; Tomoaki Natsukawa; Shunbun Kita; Yuya Fujishima; Hirotaka Sawano; Hitoshi Nishizawa; Iichiro Shimomura
    Journal of Atherosclerosis and Thrombosis 29 12 1823 - 1834 2022年12月 [査読有り]
  • Tomonori Okita; Shunbun Kita; Shiro Fukuda; Keita Fukuoka; Emi Kawada-Horitani; Masahito Iioka; Yuto Nakamura; Yuya Fujishima; Hitoshi Nishizawa; Dan Kawamori; Taka-Aki Matsuoka; Maeda Norikazu; Iichiro Shimomura
    iScience 25 11 105404 - 105404 2022年11月 [査読有り]
     
    Endogenous humoral factors that link systemic and/or local insulin demand to pancreatic β-cells have not been identified. Here, we demonstrated that T-cadherin, a unique glycosylphosphatidylinositol-anchored cadherin primarily expressed in vascular endothelial cells and cardiac and skeletal muscle cells, but not in pancreatic β-cells, was secreted as soluble forms and was important for β-cell proliferation. Cdh13 (T-cadherin) knockout mice exhibited impaired glucose handling due to attenuated β-cell proliferation under high-fat diet conditions. The gene expression analyses indicated the impairment in cell cycle and Notch signaling in the islets of T-cadherin knockout mice under high-fat diet conditions. In streptozotocin-induced diabetes, the replacement of soluble T-cadherin improved β-cell mass and blood glucose levels in T-cadherin knockout mice. Recombinant soluble T-cadherin upregulated Notch signaling in cultured murine islets. We concluded that soluble T-cadherin could work as an endogenous humoral factor whose signaling pathways including Notch signaling regulate β-cell proliferation under diabetic conditions in mice.
  • 可溶性T-カドヘリンはNotchシグナルの増幅を介して膵β細胞の増殖を促進する
    沖田 朋憲; 喜多 俊文; 福田 士郎; 福岡 啓太; 堀谷 恵美; 藤島 裕也; 西澤 均; 前田 法一; 下村 伊一郎
    肥満研究 28 Suppl. 282 - 282 (一社)日本肥満学会 2022年11月
  • 減量・代謝改善手術による食行動の変化と術後の体重減少との関連性
    木村 優; 藤島 裕也; 徳澤 千恵; 西澤 均; 白波瀬 景子; 竹治 香菜; 山口 智勢; 長井 直子; 川知 祐介; 福田 士郎; 喜多 俊文; 西塔 拓郎; 宮崎 安弘; 前田 和久; 前田 法一; 土岐 祐一郎; 下村 伊一郎
    肥満研究 28 Suppl. 292 - 292 (一社)日本肥満学会 2022年11月
  • 新たな質問表を用いた肥満2型糖尿病患者におけるSemaglutide導入前後の食嗜好性の評価
    原 知之; 藤島 裕也; 川知 祐介; 福田 士郎; 木村 優; 竹治 香菜; 山口 智勢; 徳澤 千恵; 長井 直子; 喜多 俊文; 西澤 均; 前田 法一; 下村 伊一郎
    肥満研究 28 Suppl. 295 - 295 (一社)日本肥満学会 2022年11月
  • 栄養疫学エビデンスに基づく調理指導を含めた生活習慣改善プログラムの開発とその検証
    馬殿 恵; 加藤 更紗; 仁木 暁子; 満塩 研人; 木村 優; 原 知之; 川知 祐介; 小澤 栄稔; 藤島 裕也; 山口 智勢; 長井 直子; 小澤 純二; 西澤 均; 前田 法一; 下村 伊一郎
    肥満研究 28 Suppl. 297 - 297 (一社)日本肥満学会 2022年11月
  • 2番染色体p25.3末端欠損が原因と考えられた遺伝性肥満の一例
    坂上 貴章; 小幡 佳也; 藤島 裕也; 小澤 純二; 西澤 均; 前田 法一; 山本 俊至; 下村 伊一郎
    肥満研究 28 Suppl. 310 - 310 (一社)日本肥満学会 2022年11月
  • 小児肥満にて栄養食事指導を開始し、成人後再開した高度肥満2型糖尿病の一症例
    徳澤 千恵; 長井 直子; 室岡 響; 朝山 優; 森田 隆介; 石井 純玲; 佐草 小夏; 臼井 美緒; 石橋 怜奈; 花井 美夢; 山口 智勢; 白波瀬 景子; 山本 美紀子; 福田 士郎; 藤島 裕也; 西澤 均; 前田 法一; 下村 伊一郎
    肥満研究 28 Suppl. 332 - 332 (一社)日本肥満学会 2022年11月
  • Shingo Fujita; Hitoshi Nishizawa; Yohei Miyashita; Tasuku Imada; Takashi Yamaguchi; Takeyoshi Murano; Hideaki Bujo; Yoshihiro Asano; Junji Kozawa; Norikazu Maeda; Iichiro Shimomura
    Endocrine journal 69 9 1101 - 1108 2022年09月 [査読有り]
     
    Hypertriglyceridemia is caused not only by environmental factors but also by genetic factors. Severe hypertriglyceridemia is prone to complications of acute pancreatitis. Here, we report a whole-exome sequencing (WES) analysis for a young hypertriglyceridemic patient with recurrent acute pancreatitis and the patient's mother. A 28-year-old hypertriglyceridemic female was admitted to our hospital. At 23 years old, a health checkup clarified her hypertriglyceridemia. At the age of 26 and 27, she had repeated acute pancreatitis with severe hypertriglyceridemia (serum triglyceride level were 3,888 mg/dL and 12,080 mg/dL, respectively). The patient's BMI was 29.0 kg/m2, and blood samples under fibrate medication showed triglyceride 451 mg/dL and HbA1c 7.2%. Type V dyslipidemia became more apparent at postprandial state. The WES analysis showed that the patients had two heterozygous variants in Apolipoprotein A5 (APOA5) gene (p.G185C and p.V153M), a heterozygous variant in Apolipoprotein E (APOE) gene (p.R176C), three heterozygous variants in Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene (p.T1220I, p.R1453W and p.V470M). On the other hand, her mother, who had moderate hypertriglyceridemia without acute pancreatitis, had a heterozygous variant in APOA5 gene (p.G185C) and two heterozygous variants in CFTR gene (p.T1220I and p.V470M). These results suggest that the more severe pathology of the patient than her mother might be due to the possible compound heterozygous APOA5 variants, the heterozygous APOE variant, and the possible compound heterozygous CFTR variants. In this case, WES analyses were useful to evaluate not only the causative genes of hypertriglyceridemia (APOA5 and APOE) but also the genes involved in the development of acute pancreatitis (CFTR) simultaneously.
  • 123I-MIBGの高集積を認め褐色細胞腫を疑った散発性副腎髄質過形成の1例
    脇田 哲平; 波多野 浩士; 堀谷 弘; 竹澤 健太郎; 福原 慎一郎; 藤田 和利; 植村 元秀; 木内 寛; 今村 亮一; 野々村 祝夫; 前田 法一; 西澤 均; 向井 康祐; 大月 道夫
    泌尿器科紀要 68 8 282 - 282 泌尿器科紀要刊行会 2022年08月
  • Masaki Kobayashi; Yuichiro Nezu; Mayu Itoh; Rio Uchida; Tomoya Arikawa; Minami Otsubo; Yuka Nozaki; Ryoma Tagawa; Yuya Fujishima; Norikazu Maeda; Iichiro Shimomura; Yoshikazu Higami
    Experimental gerontology 164 111821 - 111821 2022年07月 [査読有り]
     
    Adiponectin (APN), a major adipokine secreted from white adipose tissue, prevents inflammation and improves insulin sensitivity. APN exists as distinct multimeric complexes with different physiological activities, including low, middle and high molecular weight complexes (LMW, MMW and HMW, respectively) in peripheral blood. Caloric restriction (CR), an intervention that suppresses aging-related pathophysiological changes and extends lifespan, reportedly elevates the expression levels of Adipoq (encoding APN) and total circulating APN. Circulating APN levels have generally been measured using ELISA, but ELISA fails to directly and separately detect APN multimeric complexes other than HMW. Here, we aimed to evaluate the association of aging and CR with oligomerization of APN in rodent models, using immunoblotting to distinguish multimeric complexes based on molecular sizes. In mice, aging elevated plasma levels of HMW and MMW, while CR only elevated HMW. In contrast, LMW and monomeric APN levels were unchanged, suggesting that aging and CR can induce the assembly of APN oligomers in adipocytes. In rats, plasma levels of all multimeric complexes and monomeric APN were not significantly changed by aging or CR. Collectively, levels of circulating APN in mice were consistent with previous findings, whereas those of rats were partially inconsistent, probably because of experimental differences. Moreover, aging reduced Adipoq mRNA levels in mice and rats, while CR prevented this reduction only in rats. Such a discrepancy between Adipoq expression and circulating APN levels may be attributed to proteasomal regulation in adipocytes or tissue accumulation of APN. In conclusion, this study provides new findings of aging- and CR-related changes of each APN multimeric complex and underscores the importance of qualitative approaches for a greater understanding of physiological changes in APN.
  • Emi Kawada-Horitani; Shunbun Kita; Tomonori Okita; Yuto Nakamura; Hiroyuki Nishida; Yoichi Honma; Shiro Fukuda; Yuri Tsugawa-Shimizu; Junji Kozawa; Takaaki Sakaue; Yusuke Kawachi; Yuya Fujishima; Hitoshi Nishizawa; Miyuki Azuma; Norikazu Maeda; Iichiro Shimomura
    Diabetologia 65 7 1185 - 1197 2022年07月 [査読有り]
     
    AIMS/HYPOTHESIS: Immunomodulators blocking cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) have improved the treatment of a broad spectrum of cancers. These immune checkpoint inhibitors (ICIs) reactivate the immune system against tumour cells but can also trigger autoimmune side effects, including type 1 diabetes. Mesenchymal stem cell (MSC) therapy is the most prevalent cell therapy, with tissue-regenerating, anti-fibrosis and immunomodulatory functions provided by the secretome of the cells. Here, we examined whether systemic MSC treatment could prevent the development of type 1 diabetes in a NOD mouse model. METHODS: The purified PD-L1 monoclonal antibody was administered to induce diabetes in male NOD mice which normally do not develop diabetes. Human adipose-derived MSCs were administered by tail vein injections. T cells, macrophages and monocyte-derived macrophages expressing C-X-C motif chemokine ligand 9 (CXCL9) in pancreatic sections of NOD mice and a cancer patient who developed diabetes following the ICI treatments were analysed by immunofluorescence. Tissue localisation of the injected MSCs, plasma exosome levels and plasma cytokine profiles were also investigated. RESULTS: PD-1/PD-L1 blockade induced diabetes in 16 of 25 (64%) NOD mice which received anti-PD-L1 mAb without hMSCs [MSC(-)], whereas MSC administration decreased the incidence to four of 21 (19%) NOD mice which received anti-PD-L1 mAb and hMSCs [MSC(+)]. The PD-1/PD-L1 blockade significantly increased the area of CD3-positive T cells (6.2-fold) and macrophage-2 (Mac-2) antigen (2.5-fold)- and CXCL9 (40.3-fold)-positive macrophages in the islets. MSCs significantly reduced T cell (45%) and CXCL9-positive macrophage (67%) accumulation in the islets and the occurrence of diabetes. The insulin content (1.9-fold) and islet beta cell area (2.7-fold) were also improved by MSCs. T cells and CXCL9-positive macrophages infiltrated into the intricate gaps between the beta cells in the islets by PD-1/PD-L1 blockade. Such immune cell infiltration was largely prevented by MSCs. The most striking difference was observed in the CXCL9-positive macrophages, which normally did not reside in the beta cell region in the islets but abundantly accumulated in this area after PD-1/PD-L1 blockade and were prevented by MSCs. The CXCL9-positive macrophages were also observed in the islets of a cancer patient who developed diabetes following the administration of ICIs but few CXCL9-positive macrophages were observed in a control patient. Mechanistically, the injected MSCs accumulated in the lung but not in the pancreas and strongly increased plasma exosome levels and changed plasma cytokine profiles. CONCLUSIONS/INTERPRETATION: Our results suggest that MSCs can prevent the incidence of diabetes associated with immune checkpoint cancer therapy and may be worth further consideration for new adjuvant cell therapy.
  • Noriko Marutani; Shoshin Akamine; Daisuke Kanayama; Shiho Gotoh; Kanta Yanagida; Riki Maruyama; Kohji Mori; Tesshin Miyamoto; Hiroyoshi Adachi; Yukako Sakagami; Kenji Yoshiyama; Maki Hotta; Aki Nagase; Junji Kozawa; Norikazu Maeda; Michio Otsuki; Takaaki Matsuoka; Hiromi Iwahashi; Iichiro Shimomura; Norihito Murayama; Hiroshi Watanabe; Manabu Ikeda; Ichiro Mizuta; Takashi Kudo
    Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society 22 3 353 - 359 2022年05月 [査読有り]
     
    BACKGROUND: Patients with diabetes are at a higher risk for cognitive decline. Thus, biomarkers that can provide early and simple detection of cognitive decline are required. Neurofilament light chain (NfL) is a cytoskeletal protein that constitutes neural axons. Plasma NfL levels are elevated when neurodegeneration occurs. Here, we investigated whether plasma NfL levels were associated with cognitive decline in patients with type 2 diabetes. METHOD: This study included 183 patients with type 2 diabetes who visited Osaka University Hospital. All participants were tested for cognitive function using the Mini-Mental State Examination (MMSE) and the Rivermead Behavioural Memory Test (RBMT). NfL levels were analysed in the plasma and the relationship between NfL and cognitive function was examined. RESULTS: Lower RBMT-standardized profile scores (SPS) or MMSE scores correlated with higher plasma NfL levels (one-way analysis of variance: MMSE, P = 0.0237; RBMT-SPS, P = 0.0001). Furthermore, plasma NfL levels (β = -0.34, P = 0.0005) and age (β = -0.19, P = 0.016) were significantly associated with the RBMT score after multivariable regression adjustment. CONCLUSIONS: Plasma NfL levels were correlated with mild cognitive decline which is detected by the RBMT but not the MMSE in patients with type 2 diabetes. This suggests that plasma NfL levels may provide a valuable clinical tool for identifying mild cognitive decline in patients with diabetes.
  • Hitoshi Nishizawa; Norikazu Maeda; Iichiro Shimomura
    Hypertension research : official journal of the Japanese Society of Hypertension 45 4 635 - 640 2022年04月 [査読有り]
     
    Hyperuricemia is caused by reduced renal/extrarenal excretion and overproduction of uric acid. It is affected by genetic predisposition related to uric acid transporters and by visceral fat accumulation due to overnutrition. The typical symptomatic complication of hyperuricemia is gout caused by monosodium urate crystals. Accumulated evidence from epidemiological studies suggests that hyperuricemia is also a risk factor for hypertension, chronic kidney disease (CKD) and atherosclerotic cardiovascular disease (CVD). However, it remains to be determined whether urate-lowering therapy for asymptomatic patients with hyperuricemia is effective in preventing CKD or CVD progression. This mini review focuses mainly on recent papers investigating the relationship between hyperuricemia and CKD or CVD and studies of urate-lowering therapy. Accumulated studies have proposed mechanisms of renal damage and atherosclerosis in hyperuricemia, including inflammasome activation, decreased nitric oxide bioavailability and oxidative stress induced by uric acid, urate crystals and xanthine oxidoreductase (XOR)-mediated reactive oxygen species. Since patients with hyperuricemia are a heterogeneous population with complex pathologies, it may be important to assess whether an outcome is the result of decreasing serum uric acid levels or an inhibitory effect on XOR. To clarify the impact of hyperuricemia on CKD and CVD progression, high-quality and detailed clinical and basic science studies of hyperuricemia and purine metabolism are needed.
  • Taka-Aki Sakaue; Yuya Fujishima; Yoko Fukushima; Yuri Tsugawa-Shimizu; Shiro Fukuda; Shunbun Kita; Hitoshi Nishizawa; Barbara Ranscht; Kohji Nishida; Norikazu Maeda; Iichiro Shimomura
    Scientific reports 12 1 4159 - 4159 2022年03月 [査読有り]
     
    Adiponectin (APN), a protein abundantly secreted from adipocytes, has been reported to possess beneficial effects on cardiovascular diseases in association with its accumulation on target organs and cells by binding to T-cadherin. However, little is known about the role of APN in the development of diabetic microvascular complications, such as diabetic retinopathy (DR). Here we investigated the impact of APN on the progression of early retinal vascular damage using a streptozotocin (STZ)-induced diabetic mouse model. Our immunofluorescence results clearly showed T-cadherin-dependent localization of APN in the vascular endothelium of retinal arterioles, which was progressively decreased during the course of diabetes. Such reduction of retinal APN accompanied the early features of DR, represented by increased vascular permeability, and was prevented by glucose-lowering therapy with dapagliflozin, a selective sodium-glucose co-transporter 2 inhibitor. In addition, APN deficiency resulted in severe vascular permeability under relatively short-term hyperglycemia, together with a significant increase in vascular cellular adhesion molecule-1 (VCAM-1) and a reduction in claudin-5 in the retinal endothelium. The present study demonstrated a possible protective role of APN against the development of DR.
  • Naoto Katakami; Tomoya Mita; Norikazu Maeda; Yasunori Sato; Hirotaka Watada; Iichiro Shimomura
    Cardiovascular diabetology 21 1 19 - 19 2022年02月 [査読有り]
     
    BACKGROUND: Since sodium-glucose cotransporter 2 (SGLT2) inhibitors have a pleiotropic antiatherogenic effect, they are expected to attenuate the progression of atherosclerosis. However, whether SGLT2 inhibitors affect the tissue characteristics of the human arterial wall remains unclear. This study aimed to evaluate the effects of tofogliflozin, a selective SGLT2 inhibitor, on the tissue characteristics of the human arterial wall in type 2 diabetes (T2DM) patients without apparent cardiovascular disease (CVD). METHODS: The present study was a post hoc analysis based on data obtained from the Using Tofogliflozin for Possible Better Intervention against Atherosclerosis for Type 2 Diabetes Patients (UTOPIA) trial, which was a multicenter prospective, randomized, open-label, blinded-endpoint study conducted to evaluate the efficacy of tofogliflozin in preventing the progression of atherosclerosis in patients with T2DM. We evaluated the longitudinal change in the ultrasonic tissue characteristics of the carotid wall using gray-scale median (GSM), an established index of ultrasonic tissue characteristics. The right and left intima-medial areas were delineated, and the GSM values were evaluated (right GSM-CCA and left GSM-CCA). The average values of the right and left carotid arteries were defined as "mean GSM-CCA value." RESULTS: In a mixed-effects model for repeated measures, mean GSM-CCA, along with the right and left GSM-CCA values, did not significantly change in either the tofogliflozin (n = 168) or conventional treatment group (n = 169). In addition, the tofogliflozin and conventional treatment groups did not significantly differ regarding the change of the mean GSM-CCA (mean difference [95% CI] - 1.24[- 3.87, 1.38], P = 0.35), along with the right (mean difference [95% CI] - 2.33[- 5.70, 1.05], P = 0.18) and the left GSM-CCA (mean difference [95% CI] - 0.29 [- 3.53, 2.95], P = 0.86) values. Similar findings were obtained even after adjusting for traditional cardiovascular risk factors and/or the administration of drugs at baseline. CONCLUSIONS: The tissue characteristics of the carotid arterial wall did not change in either the tofogliflozin or conventional treatment group during the 104-week treatment period, and there was no significant difference between the treatment groups. Clinical trial registration UMIN000017607 ( https://www.umin.ac.jp/icdr/index.html ).
  • Taka-Aki Sakaue; Yoshinari Obata; Yuya Fujishima; Junji Kozawa; Michio Otsuki; Toshiyuki Yamamoto; Norikazu Maeda; Hitoshi Nishizawa; Iichiro Shimomura
    Journal of diabetes investigation 13 2 391 - 396 2022年02月 [査読有り]
     
    2p25.3 deletion syndrome is a rare genetic disorder that accompanies various phenotypic features, including early-onset obesity and intellectual disability. Here we report the first Japanese case of this deletion associated with severe obesity and diabetes mellitus. Microarray-based comparative genomic hybridization analysis identified a 3.1-Mb deletion of distal chromosome band 2p25.3, which was suspected as de novo. She also presented bilateral cataracts and adolescent-onset muscular weakness of upper limbs, both of which were uncommon in previously reported cases. Possibly, these symptoms are also important clinical features suggestive of this syndrome.
  • Yusuke Kawachi; Yuya Fujishima; Hitoshi Nishizawa; Takashi Nakamura; Seigo Akari; Takayo Murase; Takuro Saito; Yasuhiro Miyazaki; Hirofumi Nagao; Shiro Fukuda; Shunbun Kita; Naoto Katakami; Yuichiro Doki; Norikazu Maeda; Iichiro Shimomura
    JCI insight 6 17 2021年09月 [査読有り]
     
    Xanthine oxidoreductase (XOR) is an enzyme that catalyzes hypoxanthine to xanthine and xanthine to uric acid, respectively. However, the underlying mechanisms of increased plasma XOR and its pathological roles in systemic diseases, such as atherosclerosis, are not fully understood. In this study, we found that changes in plasma XOR activity after bariatric surgery closely associated with those in liver enzymes, but not with those in BMI. In a mouse model of nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH), plasma XOR activity markedly increased. Besides, purine catabolism was accelerated in the plasma per se of NASH mice and human patients with high XOR activity. In our NASH mice, we observed an increased vascular neointima formation consisting of dedifferentiated vascular smooth muscle cells (SMCs), which was significantly attenuated by topiroxostat, a selective XOR inhibitor. In vitro, human liver S9-derived XOR promoted proliferation of SMCs with phenotypic modulation and induced ROS production by catabolizing hypoxanthine released from human endothelial cells. Collectively, the results from human and mouse models suggest that increased plasma XOR activity, mainly explained by excess hepatic leakage, was involved in the pathogenesis of vascular injury, especially in NAFLD/NASH conditions.
  • Yusuke Kawachi; Yuya Fujishima; Hitoshi Nishizawa; Hirofumi Nagao; Takashi Nakamura; Seigo Akari; Takayo Murase; Naohiro Taya; Kazuo Omori; Akimitsu Miyake; Shiro Fukuda; Mitsuyoshi Takahara; Shunbun Kita; Naoto Katakami; Norikazu Maeda; Iichiro Shimomura
    Journal of diabetes investigation 12 8 1512 - 1520 2021年08月 [査読有り]
     
    AIMS/INTRODUCTION: Xanthine oxidoreductase (XOR) is an enzyme that catalyzes hypoxanthine and xanthine to xanthine and uric acid, respectively. Plasma XOR activity has recently been measured in humans. However, limited information is known about plasma XOR activity in patients with type 2 diabetes mellitus, and its changes after short-term glycemic control treatment. MATERIALS AND METHODS: We enrolled 28 Japanese patients (10 men/18 women) with type 2 diabetes mellitus who were hospitalized to undergo medical treatment for diabetes. Plasma XOR activity, quantified using triple quadrupole mass spectrometry and liquid chromatography, and other clinical parameters were examined at admission and 2 weeks after treatment during hospitalization. Changes in plasma XOR activity after treatment during hospitalization and associated clinical parameters were assessed. RESULTS: At the time of admission, the median plasma XOR activity was 83.1 pmol/h/mL, with a wide range of 14.4-1150 pmol/h/mL. Multiple regression analysis identified serum aspartate transaminase and alanine transaminase levels as significant and independent factors correlating with the baseline plasma XOR. Two weeks of treatment during hospitalization was associated with a significant decrease in plasma XOR activity. Changes in serum aspartate transaminase were also the only significant and independent factor correlating with changes in plasma XOR activity. CONCLUSIONS: A close relationship was observed between plasma XOR activity and liver transaminases in patients with type 2 diabetes mellitus, cross-sectionally, and also across treatment during hospitalization.
  • Maiko Shikama; Nao Sonoda; Akiko Morimoto; Sayaka Suga; Tetsuya Tajima; Junji Kozawa; Norikazu Maeda; Michio Otsuki; Taka-Aki Matsuoka; Iichiro Shimomura; Yuko Ohno
    Journal of diabetes investigation 12 6 1007 - 1014 2021年06月 [査読有り]
     
    AIMS/INTRODUCTION: Crossing capillaries in the finger nailfold might potentially be a novel diabetic retinopathy (DR) biomarker that could be assessed non-invasively in the clinical setting. However, the association between crossing capillaries and DR is controversial. This study aimed to investigate the association between the percentage of crossing capillaries in the finger nailfold and DR in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: This cross-sectional study enrolled 108 type 2 diabetes mellitus patients (aged 40-75 years) who visited the outpatient diabetic clinic at Osaka University Hospital, Osaka, Japan, between May and October 2019. Capillary morphology was assessed using nailfold capillaroscopy based on the simple capillaroscopic definitions of the European League Against Rheumatism Study Group. Details of DR and other laboratory data were obtained from medical records. The association between the tertile of the percentage of the crossing capillary and DR was analyzed using multivariable logistic regression. RESULTS: After adjusting for age, sex, diabetes duration, glycated hemoglobin, systolic blood pressure, body mass index, and use of renin-angiotensin system inhibitor and antihyperlipidemic medication, the percentage of crossing capillaries was significantly associated with DR (multivariable-adjusted odds ratios for increasing tertiles of the percentage of crossing capillary: 1 [reference], 2.05 [95% confidence interval 0.53-7.94], and 4.33 [95% confidence interval 1.16-16.21]; P-trend = 0.028). CONCLUSIONS: A higher percentage of crossing capillaries in the nailfold was associated with a higher risk of DR, independent of traditional risk and inhibiting factors, in patients with type 2 diabetes mellitus.
  • Shiro Fukuda; Shunbun Kita; Kazuya Miyashita; Masahito Iioka; Jun Murai; Tadashi Nakamura; Hitoshi Nishizawa; Yuya Fujishima; Jun Morinaga; Yuichi Oike; Norikazu Maeda; Iichiro Shimomura
    The Journal of clinical endocrinology and metabolism 106 5 1333 - 1344 2021年04月 [査読有り]
     
    CONTEXT: T-cadherin (T-cad) is a glycosylphosphatidylinositol (GPI)-anchored cadherin that mediates adiponectin to induce exosome biogenesis and secretion, protect cardiovascular tissues, promote muscle regeneration, and stimulate therapeutic heart protection by transplanted mesenchymal stem cells. CDH13, the gene locus of T-cad, affects plasma adiponectin levels most strongly, in addition to affecting cardiovascular disease risk and glucose homeostasis. Recently, it has been suggested that T-cad exists in human serum, although the details are still unclear. OBJECTIVE: To validate the existence of T-cad forms in human serum and investigate the association with clinical parameters of type 2 diabetes patients. METHODS: Using newly developed monoclonal antibodies against T-cad, pooled human serum was analyzed, and novel T-cad enzyme-linked immunosorbent assays (ELISAs) were developed. The serum T-cad concentrations of 183 Japanese type 2 diabetes patients were measured in a cross-sectional observational study. The main outcome measure was the existence of soluble T-cad in human serum. RESULTS: There were 3 forms of soluble T-cad: a 130-kDa form with a prodomain, a 100-kDa mature form, and a 30-kDa prodomain in human serum. Using newly developed ELISAs to measure them simultaneously, we found that the 130-kDa form of T-cad positively correlated with plasma adiponectin (r = 0.28, P < .001), although a physiological interaction with adiponectin was not observed in serum. The unique 30-kDa prodomain was associated with several clinical parameters in diabetes patients. CONCLUSION: We identified 3 novel forms of soluble T-cad. Their importance as disease markers and/or biomarkers of adiponectin function and the possible bioactivity of the respective molecules require further investigation.
  • Takaaki Sakaue; Yosuke Okuno; Kosuke Mukai; Shingo Fujita; Junji Kozawa; Hitoshi Nishizawa; Taka-Aki Matsuoka; Hiromi Iwahashi; Maeda Norikazu; Yuto Yamazaki; Hironobu Sasano; Michio Otsuki; Iichiro Shimomura
    Case reports in endocrinology 2021 8860498 - 8860498 2021年02月 [査読有り]
     
    A 67-year-old Japanese woman who had end-stage renal disease was referred to our hospital for kidney transplantation. Abdominal CT revealed a large adrenal mass with inhomogeneity. She had a history of hospitalization for stroke and heart failure and exhibited prominent hyporeninemic hyperaldosteronism. Histological examination of the resected tumor with anti-CYP11B2 antibody indicated that she had a vascular endothelial cyst with primary aldosteronism (PA) due to multiple adrenocortical micronodules. This report implicates the pathological interaction between adrenal vascular cysts and PA-mediated vascular damage of the adrenal vein.
  • Yuri Tsugawa-Shimizu; Yuya Fujishima; Shunbun Kita; Satoshi Minami; Taka-Aki Sakaue; Yuto Nakamura; Tomonori Okita; Yusuke Kawachi; Shiro Fukada; Tomoko Namba-Hamano; Yoshitsugu Takabatake; Yoshitaka Isaka; Hitoshi Nishizawa; Barbara Ranscht; Norikazu Maeda; Iichiro Shimomura
    American journal of physiology. Endocrinology and metabolism 320 2 E179-E190  2021年02月 [査読有り]
     
    Adiponectin (APN) is a circulating protein specifically produced by adipocytes. Native APN specifically binds to T-cadherin, a glycosylphosphatidylinositol-anchored protein, mediating the exosome-stimulating effects of APN in endothelial, muscle, and mesenchymal stem cells. It was previously reported that APN has beneficial effects on kidney diseases, but the role of T-cadherin has not been clarified yet. Here, our immunofluorescence study indicated the existence of both T-cadherin and APN protein in pericytes, subsets of tissue-resident mesenchymal stem/progenitor cells positive for platelet-derived growth factor receptor β (PDGFRβ), surrounding peritubular capillaries. In an acute renal ischemia-reperfusion (I/R) model, T-cadherin-knockout (Tcad-KO) mice, similar to APN-KO mice, exhibited the more progressive phenotype of renal tubular damage and increased vascular permeability than wild-type mice. In addition, in response to I/R-injury, the renal PDGFRβ-positive cell area increased in wild-type mice, but opposingly decreased in both Tcad-KO and APN-KO mice, suggesting severe pericyte loss. Mouse primary pericytes also expressed T-cadherin. APN promoted exosome secretion in a T-cadherin-dependent manner. Such exosome production from pericytes may play an important role in maintaining the capillary network and APN-mediated inhibition of renal tubular injury. In summary, our study suggested that APN protected the kidney in an acute renal injury model by binding to T-cadherin.NEW & NOTEWORTHY In the kidney, T-cadherin-associated adiponectin protein existed on peritubular capillary pericytes. In an acute renal ischemia-reperfusion model, deficiency of adiponectin or T-cadherin exhibited the more progressive phenotype of renal tubular damage and increased vascular permeability, accompanied by severe pericyte loss. In vitro, adiponectin promoted exosome secretion from mouse primary pericytes in a T-cadherin-dependent manner. Adiponectin plays an important role in maintaining the capillary network and amelioration of renal tubular injury by binding to T-cadherin.
  • Maiko Shikama; Nao Sonoda; Akiko Morimoto; Sayaka Suga; Tetsuya Tajima; Junji Kozawa; Norikazu Maeda; Michio Otsuki; Taka-Aki Matsuoka; Iichiro Shimomura; Yuko Ohno
    Diabetology international 12 3 260 - 267 2021年01月 [査読有り]
     
    Aim: Increased crossing of finger nailfold capillaries could be a novel visual marker of early microvascular damage among type 2 diabetes mellitus patients. Although abdominal obesity is an important driver of early microvascular damage, its association with an increase in the percentage of crossing capillaries remains uncertain. We investigated the association between abdominal obesity and an increase in the percentage of crossing capillaries in the finger nailfold in patients with type 2 diabetes mellitus. Methods: This cross-sectional study enrolled 123 type 2 diabetes mellitus patients (age 40-75 years) who visited the outpatient diabetic clinic at Osaka University Hospital between May and October 2019. Abdominal obesity was defined as a waist circumference ≥ 90 cm in women and ≥ 85 cm in men. Capillary morphology was assessed by nailfold capillaroscopy based on the simple capillaroscopic definitions of the European League Against Rheumatism Study Group. The association between abdominal obesity and a high percentage of crossing capillaries in the finger nailfold (defined as the highest tertile of crossing capillaries) was analyzed using multivariable logistic regression. Results: After adjusting for age, sex, smoking status, regular exercise, duration of diabetes, glycated hemoglobin, hypertension, and dyslipidemia, abdominal obesity was significantly associated with a high percentage of crossing capillaries (multivariable-adjusted odds ratios [95% confidence interval] = 2.70 [1.05-6.90], p = 0.038). Conclusions: Abdominal obesity may play an important role in the increase in the percentage of crossing capillaries in the finger nailfold in patients with type 2 diabetes mellitus.
  • Yoshimitsu Tanaka; Shunbun Kita; Hitoshi Nishizawa; Shiro Fukuda; Yuya Fujishima; Yoshinari Obata; Hirofumi Nagao; Shigeki Masuda; Yuto Nakamura; Yuri Shimizu; Ryohei Mineo; Tomoaki Natsukawa; Tohru Funahashi; Barbara Ranscht; So ichiro Fukada; Norikazu Maeda; Iichiro Shimomura
    Scientific Reports 10 1 2020年12月 
    An amendment to this paper has been published and can be accessed via a link at the top of the paper.
  • Shoshin Akamine; Noriko Marutani; Daisuke Kanayama; Shiho Gotoh; Riki Maruyama; Kanta Yanagida; Yukako Sakagami; Kohji Mori; Hiroyoshi Adachi; Junji Kozawa; Norikazu Maeda; Michio Otsuki; Takaaki Matsuoka; Hiromi Iwahashi; Iichiro Shimomura; Manabu Ikeda; Takashi Kudo
    Scientific reports 10 1 20350 - 20350 2020年11月 [査読有り]
     
    Neurofilament light chain (NfL) is a novel biomarker of neurodegenerative diseases. It is detectable in the peripheral blood, allowing low-invasive assessment of early signs of neurodegeneration. The level of NfL gradually increases with age; however, what other factors affect it remains unclear. The present study examined the association between blood NfL level and renal function among healthy participants undergoing a health check (n = 43, serum NfL) and patients with diabetes mellitus (n = 188, plasma NfL). All participants were 60 years of age or older; none were diagnosed with dementia. In each group, levels of blood NfL and serum creatinine significantly correlated (coefficient r = 0.50, 0.56). These associations remained statistically significant even after adjustment for age, sex, and body mass index. These findings indicate that blood NfL level might be partially affected by renal function. We recommend measuring renal function for a more precise evaluation of neuroaxonal damage, in particular, among older adults.
  • Yuto Nakamura; Shunbun Kita; Yoshimitsu Tanaka; Shiro Fukuda; Yoshinari Obata; Tomonori Okita; Hiroyuki Nishida; Yuki Takahashi; Yusuke Kawachi; Yuri Tsugawa-Shimizu; Yuya Fujishima; Hitoshi Nishizawa; Yoshinobu Takakura; Shigeru Miyagawa; Yoshiki Sawa; Norikazu Maeda; Iichiro Shimomura
    Molecular therapy : the journal of the American Society of Gene Therapy 28 10 2203 - 2219 2020年10月 [査読有り]
     
    Mesenchymal stem/stromal cells (MSCs) are cultured adult stem cells that originally reside in virtually all tissues, and the gain of MSCs by transplantation has become the leading form of cell therapy in various diseases. However, there is limited knowledge on the alteration of its efficacy by factors in recipients. Here, we report that the cardioprotective properties of intravenously injected MSCs in a mouse model of pressure-overload heart failure largely depend on circulating adiponectin, an adipocyte-secreted factor. The injected MSCs exert their function through exosomes, extracellular vesicles of endosome origin. Adiponectin stimulated exosome biogenesis and secretion through binding to T-cadherin, a unique glycosylphosphatidylinositol-anchored cadherin, on MSCs. A pharmacological or adenovirus-mediated genetic increase in plasma adiponectin enhanced the therapeutic efficacy of MSCs. Our findings provide novel insights into the importance of adiponectin in mesenchymal-progenitor-mediated organ protections.
  • Hirotaka Watanabe; Sho Yoneda; Yuichi Motoyama; Kosuke Mukai; Yosuke Okuno; Junji Kozawa; Hitoshi Nishizawa; Norikazu Maeda; Michio Otsuki; Taka-Aki Matsuoka; Eiichi Morii; Hiromi Iwahashi; Iichiro Shimomura
    Internal medicine (Tokyo, Japan) 59 6 799 - 803 2020年03月 [査読有り]
     
    Gastrin regulates gastric acid secretion, and gastrin secretion itself is regulated by the negative feedback system of gastric acidity. Autoimmune gastritis (AG) is a disease where parietal cells are destroyed, resulting in decreased acid production and an elevated serum gastrin level. We herein report 2 AG cases with marked hypergastrinemia (>5,000 pg/mL). In both cases, 24-hour gastric pH monitoring showed no time when gastric pH was <2, and immunohistochemistry revealed more than 140 gastrin-positive cells per linear millimeter at the antral mucosa. This is the first report to confirm the relationship between marked hypergastrinemia and G-cell hyperplasia with AG.
  • Yuto Nakamura; Shunbun Kita; Yoshimitsu Tanaka; Shiro Fukuda; Yoshinari Obata; Tomonori Okita; Yusuke Kawachi; Yuri Tsugawa-Shimizu; Yuya Fujishima; Hitoshi Nishizawa; Shigeru Miyagawa; Yoshiki Sawa; Atsuko Sehara-Fujisawa; Norikazu Maeda; Iichiro Shimomura
    American journal of physiology. Heart and circulatory physiology 318 2 H238-H251  2020年02月 [査読有り]
     
    A disintegrin and metalloproteinase (ADAM)12 is considered to promote cardiac dysfunction based on the finding that a small-molecule ADAM12 inhibitor, KB-R7785, ameliorated cardiac function in a transverse aortic constriction (TAC) model by inhibiting the proteolytic activation of heparin-binding-EGF signaling. However, this compound has poor selectivity for ADAM12, and the role of ADAM12 in cardiac dysfunction has not yet been investigated using genetic loss-of-function mice. We revealed that ADAM12 knockout mice showed significantly more advanced cardiac hypertrophy and higher mortality rates than wild-type mice 4 wk after TAC surgery. An ADAM12 deficiency resulted in significantly more expanded cardiac fibrosis accompanied by increased collagen-related gene expression in failing hearts. The results of a genome-wide transcriptional analysis suggested a strongly enhanced focal adhesion- and fibrosis-related signaling pathway in ADAM12 knockout hearts. The loss of ADAM12 increased the abundance of the integrinβ1 subunit and transforming growth factor (TGF)-β receptor types I and III, and this was followed by the phosphorylation of focal adhesion kinase, Akt, mammalian target of rapamycin, ERK, and Smad2/3 in the heart, which resulted in cardiac dysfunction. The present results revealed that the loss of ADAM12 enhanced focal adhesion and canonical TGF-β signaling by regulating the abundance of the integrinβ1 and TGF-β receptors.NEW & NOTEWORTHY In contrast to a long-believed cardio-damaging role of a disintegrin and metalloproteinase (ADAM)12, cardiac hypertrophy was more severe, cardiac function was lower, and mortality was higher in ADAM12 knockout mice than in wild-type mice after transverse aortic constriction surgery. The loss of ADAM12 enhanced focal adhesion- and fibrosis-related signaling pathways in the heart, which may compromise cardiac function. These results provide insights for the development of novel therapeutics that target ADAM12 to treat heart failure.
  • Norikazu Maeda; Tohru Funahashi; Yuji Matsuzawa; Iichiro Shimomura
    Atherosclerosis 292 1 - 9 2020年01月 [査読有り]
     
    Visceral fat accumulation has a marked impact on atherosclerotic cardiovascular diseases and metabolic syndrome clustering diabetes, dyslipidemia, and hypertension. Adiponectin, an adipocyte-derived circulating protein, is a representative adipocytokine and uniquely possesses two major properties: 1) its circulating concentration is approximately 3-6 orders of magnitude greater than ordinary hormones and cytokines; 2) its concentration inversely correlates with body fat mass despite its adipocyte-specific production. Low serum levels of adiponectin correlate with cardiometabolic diseases. Extensive experimental evidence has demonstrated that adiponectin possesses multiple properties, such as anti-atherosclerotic, anti-diabetic, and anti-inflammatory activities. It has been shown to play a central role against the development of metabolic syndrome and its complications. However, even approximately 25 years after its discovery, the properties of adiponectin, including how and why it exerts multiple beneficial effects on various tissues and/or organs, remain unclear. Furthermore, the mechanisms responsible for the very high circulating concentrations of adiponectin in the bloodstream have not been elucidated. Several adiponectin-binding partners, such as AdipoR1/2, have been identified, but do not fully explain the multi-functional and beneficial properties of adiponectin. Recent advances in adiponectin research may resolve these issues. Adiponectin binds to and covers cell surfaces with T-cadherin, a unique glycosylphosphatidylinositol (GPI)-anchored cadherin. The adiponectin/T-cadherin complex enhances exosomal production and release, excreting cell-toxic products from cells, particularly in the vasculature. In this review, we discuss adiponectin and the role of the adiponectin/T-cadherin system in the maintenance of whole body homeostasis and cardiovascular protection.
  • Yuri Shimizu; Junji Kozawa; Tomoaki Hayakawa; Yasuha Sakai; Takekazu Kimura; Tetsuhiro Kitamura; Sho Murase; Hisashi Tanaka; Norikazu Maeda; Michio Otsuki; Takaaki Matsuoka; Hideki Mochizuki; Hiromi Iwahashi; Iichiro Shimomura
    Internal medicine (Tokyo, Japan) 58 23 3433 - 3439 2019年12月 [査読有り]
     
    We herein report a 28-year-old woman with type 1 diabetes with an asymptomatic pontine lesion and diabetic amyotrophy. She had suffered from diabetes from 10 years old. Treatment in a hospital reduced the hemoglobin A1c level from 14.2% to 7.2% for approximately 2 months. She suffered from acute-onset pain and weakness of the lower limb muscles without central nervous system manifestations. Magnetic resonance imaging showed high-intensity lesions at the brainstem and lower limb muscles on T2-weighted images. These findings and symptoms gradually resolved. Rapid treatment of poor glycemic control might increase the risk of asymptomatic pontine lesions and diabetic amyotrophy.
  • Reiko Hayashi; Daisuke Tamada; Masahiko Murata; Tetsuhiro Kitamura; Kosuke Mukai; Norikazu Maeda; Michio Otsuki; Iichiro Shimomura
    The Journal of clinical endocrinology and metabolism 104 12 5814 - 5822 2019年12月 [査読有り]
     
    CONTEXT: Low serum adiponectin and high-density lipoprotein-cholesterol (HDL-C) levels are risk factors for cardiovascular disease. Patients with primary adrenal insufficiency are at higher risk of cardiovascular complications compared with healthy subjects. However, there is no information on the relationship between adiponectin and glucocorticoid replacement therapy in patients with secondary adrenal insufficiency (SAI). OBJECTIVE: To determine the effects of intrinsic adrenal function and glucocorticoid replacement therapy on serum adiponectin levels and lipid profile in patients with SAI. DESIGN: Part 1: a cross-sectional study. Part 2: a randomized, double-blind, crossover study. SETTING: Osaka University Hospital, Osaka, Japan. PATIENTS: Part 1: 58 patients diagnosed with nonfunctioning pituitary adenoma who underwent insulin tolerance test (ITT) for assessment of adrenal function. Part 2: 12 SAI patients randomly received hydrocortisone replacement therapy at a dose of 10, 20, or 30 mg/d for 4 weeks per term for three terms. OUTCOME MEASUREMENTS: Part 1: we analyzed the relationship between serum cortisol levels during ITT and serum adiponectin levels and the lipid profile. Part 2: serum adiponectin levels and lipid profile were measured every 4 weeks. RESULTS: Serum levels of adiponectin and HDL-C correlated significantly with peak cortisol levels after ITT. Serum adiponectin and HDL-C levels were significantly lower in patients with SAI than non-SAI. Serum levels of adiponectin and HDL-C increased in a hydrocortisone dose-dependent manner. CONCLUSIONS: Glucocorticoid replacement therapy increased serum levels of adiponectin, an adipose-derived anti-atherogenic factor, and HDL-C in patients with SAI.
  • Shunbun Kita; Shiro Fukuda; Norikazu Maeda; Iichiro Shimomura
    eLife 8 2019年10月 [査読有り]
     
    Adiponectin is an adipocyte-derived atypically abundant circulating factor that protects various organs and tissues through its receptors, AdipoRs, calreticulin, and T-cadherin. To identify the major binding partner of circulating native adiponectin, we expressed these receptors on the surface of HEK293 cells. Adiponectin, either that in mouse or human serum, purified from serum, or produced by mammalian cells, bound to cells expressing T-cadherin, but not to those expressing AdipoR1 or calreticulin. The stable introduction of T-cadherin and AdipoR1 into CHO cells resulted in the cell surface localization of these receptors. Native adiponectin in serum bound to cells expressing T-cadherin, not to those expressing AdipoR1. The knockdown of T-cadherin, but not AdipoRs resulted in the significant attenuation of native adiponectin binding to C2C12 myotubes. Therefore, native adiponectin binding depended on the amount of T-cadherin expressed in HEK293 cells, CHO cells, and C2C12 myotubes. Collectively, our mammalian cell-based studies suggest that T-cadherin is the major binding partner of native adiponectin in serum.
  • Shunbun Kita; Norikazu Maeda; Iichiro Shimomura
    The Journal of clinical investigation 129 10 4041 - 4049 2019年10月 [査読有り]
     
    Adipose tissue plays important roles in regulating whole-body energy metabolism through its storage function in white adipocytes and its dissipating function in brown and beige adipocytes. Adipose tissue also produces a variety of secreted factors called adipocytokines, including leptin and adiponectin. Furthermore, recent studies have suggested the important roles of extracellular vesicles of endosomal origin termed exosomes, which are secreted from adipocytes and other cells in adipose tissue and influence whole-body glucose and lipid metabolism. Adiponectin is known to be a pleiotropic organ-protective protein that is exclusively produced by adipocytes and decreased in obesity. Adiponectin accumulates in tissues such as heart, muscle, and vascular endothelium through binding with T-cadherin, a glycosylphosphatidylinositol-anchored (GPI-anchored) cadherin. Recently, adiponectin was found to enhance exosome biogenesis and secretion, leading to a decrease in cellular ceramides, excess of which is known to cause insulin resistance and cardiovascular disease phenotypes. These findings support the hypothesis that adipose tissue metabolism systemically regulates exosome production and whole-body metabolism through exosomes. This review focuses on intra-adipose and interorgan communication by exosomes, adiponectin-stimulated exosome production, and their dysregulation in metabolic diseases.
  • Positive Correlation between fasting plasma glucagon and serum C-peptide in Japanese patients with diabetes.
    Hosokawa Y; Kozawa J; Nishizawa H; Kawamori D; Maeda N; Otsuki M; Matsuoka TA; Iwahashi H; Shimomura I
    Heliyon 5 5 e01715  2019年05月 [査読有り]
  • Yasuki Nagai; Kosuke Mukai; Michio Otsuki; Takekazu Kimura; Junji Kozawa; Hitoshi Nishizawa; Norikazu Maeda; Taka-Aki Matsuoka; Hiromi Iwahashi; Akihisa Imagawa; Iichiro Shimomura
    Internal medicine (Tokyo, Japan) 58 7 949 - 953 2019年04月 [査読有り]
     
    Two diabetic women (case 1, 75 years old; case 2, 49 years old) being treated with glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) showed no suppression of cortisol secretion on a dexamethasone suppression test (DST). However, its secretion was suppressed after switching from GLP-1 RAs to insulin. We also checked the cortisol secretion by a DST in five consecutive inpatients (case 3-7) being treated with GLP-1 RAs. The coefficients of R-R interval variation at rest and during deep breathing were lower in the two false-positive cases (case 1 and 2) than in the five true-negative cases (case 3-6). GLP-1 RAs can be switched to insulin in order to eliminate the slow absorption effect of dexamethasone by GLP-1 RAs if a DST is planned in diabetic patients receiving GLP-1 RAs.
  • Mori D; Miyagawa S; Matsuura R; Sougawa N; Fukushima S; Ueno T; Toda K; Kuratani T; Tomita K; Maeda N; Shimomura I; Sawa Y
    Cardiovascular diabetology 18 1 39  2019年03月 [査読有り]
  • Shigeki Masuda; Yuya Fujishima; Norikazu Maeda; Yuri Tsugawa-Shimizu; Yuto Nakamura; Yoshimitsu Tanaka; Yoshinari Obata; Shiro Fukuda; Hirofumi Nagao; Shunbun Kita; Hitoshi Nishizawa; Iichiro Shimomura
    American journal of physiology. Endocrinology and metabolism 316 2 E239-E250  2019年02月 [査読有り]
     
    Glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) is an enzyme that specifically cleaves GPI anchors. Previous human studies suggested the relationship of GPI-PLD to insulin resistance, type 1 and type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD). However, the biological roles of GPI-PLD have not been elucidated. Here, we hypothesized that GPI-PLD impacted on lipid and glucose metabolism, especially in the liver. GPI-PLD mRNA was most highly expressed in the liver, and the hepatic mRNA level and circulating concentration of GPI-PLD were significantly augmented in diabetic mice. To investigate in vivo functions of GPI-PLD, we generated GPI-PLD knockout (GP-KO) mice. Mice lacking GPI-PLD exhibited the amelioration of glucose intolerance and hepatic steatosis under high-fat and high-sucrose diet. Furthermore, diacylglycerol (DAG) content was significantly decreased, and PKCε activity was suppressed in the livers of GP-KO mice. In vitro knockdown and overexpression experiments of GPI-PLD using rat primary hepatocytes showed the GPI-PLD-dependent regulation of intracellular DAG content. Finally, serum GPI-PLD levels were strongly and independently associated with serum alanine transaminase (R = 0.37, P = 0.0006) and triglyceride (R = 0.34, P = 0.001) levels in male subjects with metabolic syndrome. In conclusion, upregulation of hepatic GPI-PLD in diabetic conditions leads to DAG accumulation in the liver by shedding GPI anchors intracellularly, which may play a causal role in impaired hepatic insulin signaling and the progression of NAFLD.
  • Yoshimitsu Tanaka; Shunbun Kita; Hitoshi Nishizawa; Shiro Fukuda; Yuya Fujishima; Yoshinari Obata; Hirofumi Nagao; Shigeki Masuda; Yuto Nakamura; Yuri Shimizu; Ryohei Mineo; Tomoaki Natsukawa; Tohru Funahashi; Barbara Ranscht; So-Ichiro Fukada; Norikazu Maeda; Iichiro Shimomura
    Scientific reports 9 1 16 - 16 2019年01月 [査読有り]
     
    Skeletal muscle has remarkable regenerative potential and its decline with aging is suggested to be one of the important causes of loss of muscle mass and quality of life in elderly adults. Metabolic abnormalities such as obesity were linked with decline of muscle regeneration. On the other hand, plasma levels of adiponectin are decreased in such metabolic conditions. However, plasma levels of adiponectin have been shown to inversely correlate with muscle mass and strength in elderly people especially with chronic heart failure (CHF). Here we have addressed whether adiponectin has some impact on muscle regeneration after cardiotoxin-induced muscle injury in mice. Muscle regeneration was delayed by angiotensin II infusion, mimicking aging and CHF as reported. Adiponectin overexpression in vivo decreased necrotic region and increased regenerating myofibers. Such enhanced regeneration by excess adiponectin was also observed in adiponectin null mice, but not in T-cadherin null mice. Mechanistically, adiponectin accumulated on plasma membrane of myofibers both in mice and human, and intracellularly colocalized with endosomes positive for a multivesicular bodies/exosomes marker CD63 in regenerating myofibers. Purified high-molecular multimeric adiponectin similarly accumulated intracellularly and colocalized with CD63-positive endosomes and enhanced exosome secretion in differentiating C2C12 myotubes but not in undifferentiated myoblasts. Knockdown of T-cadherin in differentiating C2C12 myotubes attenuated both adiponectin-accumulation and adiponectin-mediated exosome production. Collectively, our studies have firstly demonstrated that adiponectin stimulates muscle regeneration through T-cadherin, where intracellular accumulation and exosome-mediated process of adiponectin may have some roles.
  • Jun Murai; Hitoshi Nishizawa; Akihito Otsuka; Shiro Fukuda; Yoshimitsu Tanaka; Hirofumi Nagao; Yasuna Sakai; Masahide Suzuki; Shinji Yokota; Hidetoshi Tada; Mayumi Doi; Yuya Fujishima; Shunbun Kita; Tohru Funahashi; Norikazu Maeda; Tadashi Nakamura; Iichiro Shimomura
    Cardiovascular diabetology 17 1 112 - 112 2018年08月 [査読有り]
     
    BACKGROUND: Although obesity-related type 2 diabetes mellitus (T2DM) and sarcopenia in the elderly have been increasing worldwide, the associations among visceral fat accumulation, skeletal muscle indices (mass, strength, and quality) and cardiovascular diseases in T2DM remain poorly investigated. METHODS: We enrolled 183 Japanese T2DM inpatients (126 men, 57 women; mean age 64.7 ± 12.6 years, ± SD). The estimated-visceral fat area (eVFA) and skeletal muscle mass were measured by each device using bioelectrical impedance analysis method. We also measured grip strength by dynamometer and motor nerve conduction velocity (MCV). We analyzed the difference in skeletal muscle indices between T2DM patients with and without visceral fat accumulation, and examined the impact of skeletal muscle indices on cardiovascular diseases in patients with visceral fat accumulation. RESULTS: The prevalence of sarcopenia defined by the Consensus of Asian Working Group for Sarcopenia and low skeletal muscle mass were both lower in the visceral fat accumulation (+) group than in (-) group. However, the prevalence of weak hand grip strength was similar in the visceral fat accumulation (-) and (+) groups, indicating that considerable patients with visceral fat accumulation had weak grip strength in spite of fair skeletal muscle mass. Muscle quality [grip strength (kg)/arm muscle mass (kg)] was significantly lower in patients with visceral fat accumulation. Multiple regression analysis identified eVFA, MCV and sex as significant and independent determinants of muscle quality. In visceral fat accumulation (+) group, the patients with low muscle quality had longer duration of diabetes, lower eGFR, higher serum adiponectin, lower MCV and higher prevalence of cardiovascular diseases, compared to the patients with high muscle quality. Finally, sex- and age-adjusted models showed significant association between low muscle quality and cardiovascular diseases in all subjects (odds ratio 2.28, p = 0.012), especially in patients with visceral fat accumulation (odds ratio 2.72, p = 0.018). CONCLUSIONS: T2DM patients with visceral fat accumulation had low muscle quality, and patients with low muscle quality were more affected with cardiovascular diseases.
  • Hirofumi Nagao; Hitoshi Nishizawa; Yoshimitsu Tanaka; Tadafumi Fukata; Tsunekazu Mizushima; Masahiro Furuno; Takeshi Bamba; Yu Tsushima; Yuya Fujishima; Shunbun Kita; Tohru Funahashi; Norikazu Maeda; Masaki Mori; Eiichiro Fukusaki; Iichiro Shimomura
    Obesity (Silver Spring, Md.) 26 7 1168 - 1178 2018年07月 [査読有り]
     
    OBJECTIVE: The production of uric acid in murine white adipose tissue (mWAT), and that such production was augmented in obese mice, was recently reported. However, little is known about the secretion of metabolites associated with purine catabolism in human WAT (hWAT). The present study analyzed this in hWAT. METHODS: Freshly isolated hWAT and mWAT were cultured. The secretion of metabolites associated with purine catabolism was measured. Tissue distribution profiles of genes associated with purine metabolism and metabolite profiling of adipocytes in hypoxia were analyzed. RESULTS: Secretion of hypoxanthine from hWAT was higher than those of xanthine and uric acid. On the other hand, secretion of uric acid was relatively higher than xanthine and hypoxanthine in mWAT. Xanthine oxidoreductase (XOR) mRNA expression levels in hWAT were markedly lower than that in the human liver. In murine tissues, XOR mRNA expression levels in mWAT were comparable with those in the liver. Cultured human adipocytes secreted hypoxanthine, and its secretion was increased under hypoxia. The metabolic analysis of human adipocytes showed that hypoxia increased metabolites associated with de novo biosynthesis of purine nucleotides. CONCLUSIONS: The present study revealed that hypoxanthine was secreted from human adipose tissue, and the secretion might be increased in local hypoxia.
  • Yoshinari Obata; Shunbun Kita; Yoshihisa Koyama; Shiro Fukuda; Hiroaki Takeda; Masatomo Takahashi; Yuya Fujishima; Hirofumi Nagao; Shigeki Masuda; Yoshimitsu Tanaka; Yuto Nakamura; Hitoshi Nishizawa; Tohru Funahashi; Barbara Ranscht; Yoshihiro Izumi; Takeshi Bamba; Eiichiro Fukusaki; Rikinari Hanayama; Shoichi Shimada; Norikazu Maeda; Iichiro Shimomura
    JCI insight 3 8 2018年04月 [査読有り]
     
    Adiponectin, an adipocyte-derived circulating protein, accumulates in vasculature, heart, and skeletal muscles through interaction with a unique glycosylphosphatidylinositol-anchored cadherin, T-cadherin. Recent studies have demonstrated that such accumulation is essential for adiponectin-mediated cardiovascular protection. Here, we demonstrate that the adiponectin/T-cadherin system enhances exosome biogenesis and secretion, leading to the decrease of cellular ceramides. Adiponectin accumulated inside multivesicular bodies, the site of exosome generation, in cultured cells and in vivo aorta, and also in exosomes in conditioned media and in blood, together with T-cadherin. The systemic level of exosomes in blood was significantly affected by adiponectin or T-cadherin in vivo. Adiponectin increased exosome biogenesis from the cells, dependently on T-cadherin, but not on AdipoR1 or AdipoR2. Such enhancement of exosome release accompanied the reduction of cellular ceramides through ceramide efflux in exosomes. Consistently, the ceramide reduction by adiponectin was found in aortas of WT mice treated with angiotensin II, but not in T-cadherin-knockout mice. Our findings provide insights into adiponectin/T-cadherin-mediated organ protection through exosome biogenesis and secretion.
  • Daisaku Masuda; Takuya Kobayashi; Masami Sairyou; Hiroyuki Hanada; Tohru Ohama; Masahiro Koseki; Makoto Nishida; Norikazu Maeda; Shinji Kihara; Tatsuya Minami; Koji Yanagi; Yasushi Sakata; Shizuya Yamashita
    Journal of Atherosclerosis and Thrombosis 25 6 512 - 520 2018年 [査読有り]
     
    Aim: The morbidity of cardiovascular disease in patients with type 2 diabetes mellitus (DM) deteriorates in combination with dyslipidemia. The accumulation of remnant lipoproteins in patients with fasting and postprandial hypertriglyceridemia is highly atherogenic. The current study investigated whether the dipeptidyl peptidase-4 inhibitor sitagliptin ameliorates dyslipidemia and hyperglycemia. Methods: We enrolled 38 patients with type 2 DM (20 males and 18 females, 65.7±9.9 years old, HbA1c levels < 8.4%), and all patients gave written informed consent. Sitagliptin (50 mg/day) was added to current antidiabetic treatments and increased to 100 mg/day to achieve low HbA1c levels (< 7.4%). Glucose and lipoprotein metabolism profiles were analyzed at 0, 4, and 12 weeks after sitagliptin administration. Results: Sitagliptin significantly decreased fasting levels of triglyceride (TG) (161±90 vs. 130±66 mg/dl, p< 0.01) and non-HDL-C (129±29 vs. 116±20 mg/dl, p< 0.01) in combination with glucose (150±47 vs. 129±27 mg/dl, p< 0.01) and HbA1c (7.1±0.6 vs. 6.6±0.7 mg/dl, p< 0.001). Sitagliptin also significantly decreased the fasting levels of apolipoprotein (apo) B-48 (7.8±6.7 vs. 5.6±4.0 μg/ml, p< 0.01), remnant lipoprotein cholesterol (15.3±9.5 vs. 12.0±7.9 mg/dl, p< 0.05) and other apolipoproteins, such as apoB, apoC-II, apoC-III, and apoE. Analyses of the lipoprotein profiles of fasting sera revealed that sitagliptin significantly decreased cholesterol and TG levels of lipoprotein fractions in the size of very low density lipoprotein and low density lipoprotein. Conclusions: These findings indicated that sitagliptin administration ameliorated the lipid and lipoprotein profiles in patients with diabetes, which may be due to the decrease in atherogenic remnant lipoproteins (UMIN#000013218).
  • Hiroyo Ninomiya; Naoto Katakami; Taka-Aki Matsuoka; Mitsuyoshi Takahara; Hitoshi Nishizawa; Norikazu Maeda; Michio Otsuki; Akihisa Imagawa; Hiroyasu Iso; Tetsuya Ohira; Iichiro Shimomura
    Journal of diabetes investigation 9 1 162 - 172 2018年01月 [査読有り]
     
    AIMS/INTRODUCTION: It is suggested that a positive psychosocial condition has a good effect on health and glycemic control. However, there has been no research to evaluate the association between positive psychosocial factors and diabetic nephropathy (DN). The aim of the present study was to evaluate the association between psychosocial factors and DN in patients with type 2 diabetes. MATERIAL AND METHODS: To assess psychosocial condition, six indicators (happiness score, Life Orientation Test-revised score as an indicator of dispositional optimism, laughter frequency, self-awareness of stress, social network and social support) were assessed by a self-administered questionnaire, and associations between these psychosocial indicators and the presence of DN were examined. RESULTS: A cross-sectional analysis of patients with (n = 123) and without DN (n = 220) showed that a high score for happiness (odds ratio [OR] per 1 standard deviation 0.71, 95% confidence interval [CI] 0.57-0.89, P = 0.003), high Life Orientation Test-revised score (OR per 1 standard deviation 0.77, 95% CI: 0.61-0.98, P = 0.035), less self-awareness of stress (OR 0.56, 95% CI: 0.34-0.90, P = 0.017), high connection of social network (OR 0.55, 95% CI: 0.35-0.87, P = 0.010) and high social support (OR 0.61, 95% CI: 0.38-0.96, P = 0.035) were associated with a reduced risk of prevalence of DN. Similar results were observed even after adjustment for the following conventional risk factors of DN: age, sex, duration of diabetes, hemoglobin A1c, hypertension, dyslipidemia and current smoking. CONCLUSIONS: The present study showed that five out of six prespecified indicators of psychosocial condition were significantly associated with the presence of DN in Japanese patients with type 2 diabetes.
  • Fumi Sato; Norikazu Maeda; Takayuki Yamada; Hideyuki Namazui; Shiro Fukuda; Tomoaki Natsukawa; Hirofumi Nagao; Jun Murai; Shigeki Masuda; Yoshimitsu Tanaka; Yoshinari Obata; Yuya Fujishima; Hitoshi Nishizawa; Tohru Funahashi; Iichiro Shimomura
    Circulation Journal 82 2 502 - 508 2018年 [査読有り]
     
    Background: Excess of visceral fat is a central factor in the pathogenesis of metabolic syndrome (MetS) and atherosclerosis. However, little is known about how much epicardial fat affects cardiometabolic disorders in comparison with visceral or subcutaneous fat. Methods and Results: Participants suspected as having angina pectoris underwent cardiac computed tomography (CT) imaging. Of them, 374 subjects were analyzed the association of clinical characteristics and CT-based fat distribution measured as epicardial fat volume (EFV), visceral fat area (VFA), and subcutaneous fat area (SFA). EFV was highly associated with VFA (R=0.58). Serum adiponectin was significantly decreased in high VFA subjects (VFA ≥100 cm2) and was also reduced in the high EFV group (EFV 2 ≥80 cm3). Among the low VFA groups, the numbers of subjects with diabetes and coronary atherosclerosis were increased in high EFV group. Among the low EFV groups, the numbers of subjects with diabetes, hyperuricemia, and coronary atherosclerosis were increased among the high VFA subjects. In an age-, sex-, and body mass index (BMI)-adjusted model, EFV was associated with dyslipidemia and MetS, and VFA was significantly associated with hypertension, dyslipidemia, MetS, and coronary atherosclerosis, while SFA was not related with coronary risks and atherosclerosis. Conclusions: Epicardial fat accumulation may be a risk for coronary atherosclerosis in subjects without visceral fat accumulation. Visceral fat is the strongest risk for cardiometabolic diseases among the 3 types of fat depot.
  • Shiro Fukuda; Ayumu Hirata; Hitoshi Nishizawa; Hirofumi Nagao; Takekazu Kimura; Yuya Fujishima; Masaya Yamaoka; Junji Kozawa; Akihisa Imagawa; Tohru Funahashi; Norikazu Maeda; Iichiro Shimomura
    Journal of diabetes investigation 9 1 63 - 68 2018年01月 [査読有り]
     
    Sleep pattern has been shown to be associated with type 2 diabetes mellitus. Here, we investigated the difference in bedtime, waking time and estimated sleep duration in type 2 diabetes mellitus patients with or without visceral fat accumulation, using a questionnaire on sleep patterns. The study participants were 59 Japanese type 2 diabetes mellitus patients (men/women 34/25, age 64.5 ± 12.1 years). Visceral fat accumulation was defined as estimated visceral fat area ≥100 cm2 . The patients with visceral fat accumulation (n = 40) showed significantly later bedtime (23.51 ± 01.27 h in the [+] group vs 22.49 ± 01.23 h in the [-] group) and shorter estimated sleep duration (6.6 ± 1.4 h in the [+] group vs 7.9 ± 1.0 h in the [-] group) on weekdays, compared with those without (n = 19). Later bedtime and shorter estimated sleep duration existed in the type 2 diabetes mellitus patients with visceral fat accumulation, compared with those without.
  • Mitsunobu Kubota; Masayasu Yoneda; Norikazu Maeda; Haruya Ohno; Kenji Oki; Tohru Funahashi; Iichiro Shimomura; Noboru Hattori
    CARDIOVASCULAR DIABETOLOGY 16 1 83  2017年07月 [査読有り]
     
    Background: Although Japanese-Americans and native Japanese share the same genetic predispositions, they live different lifestyles, resulting in insulin resistance in Japanese-Americans. We investigated whether the quantitative and qualitative changes in adiponectin (APN) due to differences in lifestyle contribute to the development of insulin resistance. Methods: We evaluated 325 native Japanese in Hiroshima, Japan and 304 Japanese-Americans in Los Angeles, the United States, who were aged between 30 and 70 years and underwent medical examinations between 2009 and 2010. All participants underwent a 75-g oral glucose tolerance test (OGTT) to assess their glucose tolerance. The insulin response to oral glucose load, the Matsuda index, total APN levels, and C1q-APN/total-APN ratios were compared between native Japanese and Japanese-Americans. Results: Compared with the native Japanese, the Japanese-Americans had significantly lower Matsuda index and higher area under the curve values for serum insulin concentration during OGTT in the normal glucose tolerance (NGT) and impaired glucose tolerance (IGT) groups, but not in the diabetes mellitus (DM) group. Furthermore, the Japanese-Americans had significantly lower total APN levels and higher C1q-APN/total-APN ratios than the native Japanese in the NGT and IGT groups, but not in the DM group. Conclusions: This study suggested that, in Japanese people, the westernization of their lifestyle might affect quantitative and qualitative changes in APN and induce insulin resistance.
  • Shiro Fukuda; Shunbun Kita; Yoshinari Obata; Yuya Fujishima; Hirofumi Nagao; Shigeki Masuda; Yoshimitsu Tanaka; Hitoshi Nishizawa; Tohru Funahashi; Junichi Takagi; Norikazu Maeda; Iichiro Shimomura
    JOURNAL OF BIOLOGICAL CHEMISTRY 292 19 7840 - 7849 2017年05月 [査読有り]
     
    Adiponectin, an adipocyte-derived circulating protein, accumulates in the heart, vascular endothelium, and skeletal muscles through an interaction with T-cadherin (T-cad), a unique glycosylphosphatidylinositol-anchored cadherin. Recent studies have suggested that this interaction is essential for adiponectin-mediated cardiovascular protection. However, the precise protein-protein interaction between adiponectin and T-cad remains poorly characterized. Using ELISA-based and surface plasmon analyses, we report here that T-cad fused with IgG Fc as a fusion tag by replacing its glycosylphosphatidylinositol-anchor specifically bound both hexameric and larger multimeric adiponectin with a dissociation constant of similar to 1.0 nM and without any contribution from other cellular or serum factors. The extracellular T-cad repeats 1 and 2 were critical for the observed adiponectin binding, which is required for classical cadherin-mediated cell-to-cell adhesion. Moreover, the 130-kDa prodomain-bearing T-cad, uniquely expressed on the cell surface among members of the cadherin family and predominantly increased by adiponectin, contributed significantly to adiponectin binding. Inhibition of prodomain-processing by a prohormone convertase inhibitor increased 130-kDa T-cad levels and also enhanced adiponectin binding to endothelial cells both by more preferential cell-surface localization and by higher adiponectin-binding affinity of 130-kDa T-cad relative to 100-kDa T-cad. The preferential cell-surface localization of 130-kDa T-cad relative to 100-kDa T-cad was also observed in normal mice aorta in vivo. In conclusion, our study shows that a unique key feature of the T-cad prodomain is its involvement in binding of the T-cad repeats 1 and 2 to adiponectin and also demonstrates that adiponectin positively regulates T-cad abundance.
  • Yuya Fujishima; Norikazu Maeda; Keisuke Matsuda; Shigeki Masuda; Takuya Mori; Shiro Fukuda; Ryohei Sekimoto; Masaya Yamaoka; Yoshinari Obata; Shunbun Kita; Hitoshi Nishizawa; Tohru Funahashi; Barbara Ranscht; Iichiro Shimomura
    FASEB JOURNAL 31 4 1571 - 1583 2017年04月 [査読有り]
     
    Adiponectin, an adipocyte-derived protein abundant in the circulation, is thought to be protective against atherosclerosis. However, it is not fully understood how the association of adiponectin with vascular cells and its antiatherogenic effect are connected. In this study, T-cadherin was essential for accumulation of adiponectin in the neointima and atherosclerotic plaque lesions, and the adiponectin-T-cadherin association protected against vascular injury. In the apolipoprotein E-knockout (ApoE-KO) mice, adiponectin and T-cadherin colocalized on endothelial cells and synthetic smooth muscle cells in the aortic intima. Notably, aortic adiponectin protein disappeared in T-cadherin/ApoE double-knockout (Tcad/ApoE-DKO) mice with significant elevation of blood adiponectin concentration. Furthermore, in Tcad/ApoE-DKO mice, carotid artery ligation resulted in a significant increase of neointimal thickness compared with ApoE-KO mice. Finally, on a high-cholesterol diet, Tcad/ApoE-DKO mice increased atherosclerotic plaque formation, despite a 5-fold increase in plasma adiponectin level compared with that in ApoE-KO mice. In vitro, knockdown of T-cadherin from human aortic smooth muscle cells (HASMCs) with synthetic phenotype significantly reduced adiponectin accumulation on HASMCs and negated the inhibitory effect of adiponectin on proinflammatory change. Collective evidence showed that adiponectin accumulates in the vasculature via T-cadherin, and the adiponectin-T-cadherin association plays a protective role against neointimal and atherosclerotic plaque formations.-Fujishima, Y., Maeda, N., Matsuda, K., Masuda, S., Mori, T., Fukuda, S., Sekimoto, R., Yamaoka, M., Obata, Y., Kita, S., Nishizawa, H., Funahashi, T., Ranscht, B., Shimomura, I. Adiponectin association with T-cadherin protects against neointima proliferation and atherosclerosis.
  • Hirofumi Nagao; Hitoshi Nishizawa; Takeshi Bamba; Yasumune Nakayama; Noriyoshi Isozumi; Shushi Nagamori; Yoshikatsu Kanai; Yoshimitsu Tanaka; Shunbun Kita; Shiro Fukuda; Tohru Funahashi; Norikazu Maeda; Eiichiro Fukusaki; Iichiro Shimomura
    JOURNAL OF BIOLOGICAL CHEMISTRY 292 11 4469 - 4483 2017年03月 [査読有り]
     
    Obesity is closely associated with various metabolic disorders. However, little is known about abnormalities in the metabolic change of obese adipose tissue. Here we use static metabolic analysis and in vivo metabolic turnover analysis to assess metabolic dynamics in obese mice. The static metabolic analyses showed that glutamate and constitutive metabolites of the TCA cycle were increased in the white adipose tissue (WAT) of ob/ob and diet-induced obesity mice but not in the liver or skeletal muscle of these obese mice. Moreover, in vivo metabolic turnover analyses demonstrated that these glucose-derived metabolites were dynamically and specifically produced in obese WAT compared with lean WAT. Glutamate rise in obese WAT was associated with down-regulation of glutamate aspartate transporter (GLAST), a major glutamate transporter for adipocytes, and low uptake of glutamate into adipose tissue. In adipocytes, glutamate treatment reduced adiponectin secretion and insulin-mediated glucose uptake and phosphorylation of Akt. These data suggest that a high intra-adipocyte glutamate level potentially relates to adipocyte dysfunction in obesity. This study provides novel insights into metabolic dysfunction in obesity through comprehensive application of in vivo metabolic turnover analysis in two obese animal models.
  • Tomoaki Natsukawa; Norikazu Maeda; Shiro Fukuda; Masaya Yamaoka; Yuya Fujishima; Hirofumi Nagao; Fumi Sato; Hitoshi Nishizawa; Hirotaka Sawano; Yasuyuki Hayashi; Tohru Funahashi; Tatsuro Kai; Iichiro Shimomura
    JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS 24 8 793 - 803 2017年 [査読有り]
     
    Aims: Adiponectin, an adipocyte-specific secretory protein, abundantly exists in the blood stream while its concentration paradoxically decreases in obesity. Hypoadiponectinemia is one of risks of cardiovascular diseases. However, impact of serum adiponectin concentration on acute ischemic myocardial damages has not been fully clarified. The present study investigated the association of serum adiponectin and creatine kinase (CK)-MB levels in subjects with ST-segment elevation myocardial infarction (STEMI). Methods: This study is a physician-initiated observational study and is also registered with the University Hospital Medical Information Network (Number: UMIN 000014418). Patients were admitted to Senri Critical Care Medical Center, given a diagnosis of STEMI, and treated by primary percutaneous coronary intervention (PCI). Finally, 49 patients were enrolled and the association of serum adiponectin, CK-MB, and clinical features were mainly analyzed. Results: Serum adiponectin levels decreased rapidly and reached the bottom at 24 hours after recanalization. Such reduction of serum adiponectin was inversely correlated with the area under the curve (AUC) of serum CK-MB (p=0.013). Serum adiponectin concentrations were inversely correlated with AUC of serum CK-MB. In multivariate analysis, serum adiponectin concentration on admission (p=0.002) and collateral (p=0.037) were significantly and independently correlated with serum AUC of CK-MB. Conclusion: Serum AUC of CK-MB in STEMI subjects was significantly associated with serum adiponectin concentration on admission and reduction of serum adiponectin levels from baseline to bottom. The present study may provide a possibility that serum adiponectin levels at acute phase are useful in the prediction for prognosis after PCI-treated STEMI subjects.
  • Reiko D. Hayashi; Masaya Yamaoka; Hitoshi Nishizawa; Shiro Fukuda; Yuya Fujishima; Takekazu Kimura; Jyunji Kozawa; Shunbun Kita; Taka-aki Matsuoka; Michio Otsuki; Akihisa Imagawa; Kimiyoshi Ichida; Atsuo Taniguchi; Norikazu Maeda; Tohru Funahashi; Iichiro Shimomura
    INTERNAL MEDICINE 56 9 1071 - 1077 2017年 [査読有り]
     
    A 27 year-old severely obese man (BMI, 35.1) had hyperuricemia and multiple gouty tophi with bone erosion and destruction, resulting in gait disturbance for 6 years after the early onset of gout at 21 years of age. His hyperuricemia was associated with hyperinsulinemia in obesity and a genetic variant of the ABCG2 gene. In addition, multiple gouty tophi with bone erosion and destruction might have been caused by hypoadiponectinemia and the elevation of the patient's pro-inflammatory cytokine (IL-1 beta) level with the accumulation of visceral fat. In this case, bone and Ga-67 scintigraphy were useful for detecting the location and magnitude of gouty tophi.
  • Yoshinari Obata; Norikazu Maeda; Yuya Yamada; Koji Yamamoto; Seiji Nakamura; Masaya Yamaoka; Yoshimitsu Tanaka; Shigeki Masuda; Hirofumi Nagao; Shiro Fukuda; Yuya Fujishima; Shunbun Kita; Hitoshi Nishizawa; Tohru Funahashi; Ken-Ichi Matsubara; Yuji Matsuzawa; Iichiro Shimomura
    Cardiovascular diabetology 15 1 159 - 159 2016年11月 [査読有り]
     
    Background: Visceral fat plays a central role in the development of metabolic syndrome and atherosclerotic cardiovascular diseases. The association of visceral fat accumulation with cardio-metabolic diseases has been reported, but the impact of visceral fat on the gene expression profile in peripheral blood cells remains to be determined. The aim of this study was to determine the effects of visceral fat area (VFA) and subcutaneous fat area (SFA) on the gene expression profile in peripheral blood cells of obese subjects. Methods: All 17 enrolled subjects were hospitalized to receive diet therapy for obesity (defined as body mass index, BMI, greater than 25 kg/m(2)). VFA and SFA were measured at the umbilical level by computed tomography (CT). Blood samples were subjected to gene expression profile analysis by using SurePrint G3 Human GE Microarray 8 x 60 k ver. 2.0. The correlation between various clinical parameters, including VFA and SFA, and peripheral blood gene expression levels was analyzed. Results: Among the 17 subjects, 12 had normal glucose tolerance or borderline diabetes, and 5 were diagnosed with type 2 diabetes without medications [glycated hemoglobin (HbA1c); 6.3 +/- 1.3%]. The mean BMI, VFA, and SFA were 30.0 +/- 5.5 kg/m(2), 177 +/- 67 and 245 +/- 131 cm(2), respectively. Interestingly, VFA altered the expression of 1354 genes, including up-regulation of 307 and down-regulation of 1047, under the statistical environment that the parametric false discovery rate (FDR) was less than 0.1. However, no significant effects were noted for SFA or BMI. Gene ontology analysis showed higher prevalence of VFA-associated genes than that of SFA-associated genes, among the genes associated with inflammation, oxidative stress, immune response, lipid metabolism, and glucose metabolism. Conclusions: Accumulation of visceral fat, but not subcutaneous fat, has a significant impact on the gene expression profile in peripheral blood cells in obese Japanese subjects.
  • Shijo T; Kuratani T; Shirakawa Y; Torikai K; Shimamura K; Sakamoto T; Watanabe Y; Maeda N; Tomiyama N; Sawa Y
    European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 48 6 960 - 967 2015年12月 [査読有り]
     
    OBJECTIVES: The repair of extensive thoraco-abdominal aortic aneurysms (TAAAs) is invasive and carries a high risk for spinal cord injury (SCI). The aim of this study was to assess the early results and collateral circulation to the spinal cord after hybrid repair for Crawford extent II aortic aneurysms. METHODS: Between 1997 and 2013, we performed 128 thoracic endovascular aortic repair (TEVAR) procedures for TAAAs. This study reviews 12 patients who underwent hybrid TEVAR for a Crawford extent II aortic aneurysm (mean age: 56 years, 6 men, chronic dissection: 10). Aortic arch repair was performed to create a proximal landing zone and visceral debranching bypass was performed to create a distal landing zone at separate stages prior to TEVAR. Subsequently, a stent graft was deployed to cover the residual downstream aorta. TEVAR was generally performed the day after the final debranching procedure. Cerebrospinal fluid drainage was performed, and the mean blood pressure was maintained at >90 mmHg in all cases. RESULTS: The median operation time for TEVAR was 94 min (range: 71-421 min) and the mean blood loss was 300 ml (range: 130-1350 ml). No SCI or in-hospital death was observed after TEVAR. Multidetector computed tomography identified three arteries (subclavian artery, external iliac artery and internal iliac artery) providing collateral circulation to spinal segmental arteries (SAs). In all cases, mid-thoracic SAs (Th5-8) and low lumbar SAs (L2-5) were fed by the subclavian artery and the internal iliac artery, respectively. Additionally, low thoracic to high lumbar SAs (Th9-L1) communicated with the subclavian artery via the lateral thoracic wall and/or the external iliac artery via the abdominal wall. CONCLUSIONS: We achieved satisfactory early and mid-term outcomes with hybrid repair for Crawford extent II TAAAs. Furthermore, collateral circulation to SAs was maintained during and after TEVAR regardless of the extent of the aortic repair.
  • Ryohei Sekimoto; Shiro Fukuda; Norikazu Maeda; Yu Tsushima; Keisuke Matsuda; Takuya Mori; Hideaki Nakatsuji; Hitoshi Nishizawa; Ken Kishida; Junichi Kikuta; Yumiko Maijima; Tohru Funahashi; Masaru Ishii; Iichiro Shimomura
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 112 16 E2058 - E2066 2015年04月 [査読有り]
     
    Chronic low-grade inflammation of adipose tissue plays a crucial role in the pathophysiology of obesity. Immunohistological microscopic analysis in obese fat tissue has demonstrated the infiltration of several immune cells such as macrophages, but dynamics of immune cells have not been fully elucidated and clarified. Here, by using intravital multiphoton imaging technique, to our knowledge for the first time, we analyzed and visualized the inflammatory processes in adipose tissue under high-fat and high-sucrose (HF/HS) diet with lysozyme M-EGFP transgenic (LysM(EGFP)) mice whose EGFP was specifically expressed in the myelomonocytic lineage. Mobility of LysM(EGFP)-positive macrophages was shown to be activated just 5 d after HF/HS diet, when the distinct hypertrophy of adipocytes and the accumulation of macrophages still have not become prominent. Significant increase of S100A8 was detected in mature adipocyte fraction just 5 d after HF/HS diet. Recombinant S100A8 protein stimulated chemotactic migration in vitro and in vivo, as well as induced proinflammatory molecules, both macrophages and adipocytes, such as TNF-alpha and chemokine (C-C motif) ligand 2. Finally, an antibody against S100A8 efficiently suppressed the HF/HS diet-induced initial inflammatory change, i.e., increased mobilization of adipose LysM(EGFP)-positive macrophages, and ameliorated HF/HS diet-induced insulin resistance. In conclusion, time-lapse intravital multiphoton imaging of adipose tissues identified the very early event exhibiting increased mobility of macrophages, which may be triggered by increased expression of adipose S100A8 and results in progression of chronic inflammation in situ.
  • Keisuke Matsuda; Yuya Fujishima; Norikazu Maeda; Takuya Mori; Ayumu Hirata; Ryohei Sekimoto; Yu Tsushima; Shigeki Masuda; Masaya Yamaoka; Kana Inoue; Hitoshi Nishizawa; Shunbun Kita; Barbara Ranscht; Tohru Funahashi; Iichiro Shimomura
    ENDOCRINOLOGY 156 3 934 - 946 2015年03月 [査読有り]
     
    Adiponectin (Adipo), a multimeric adipocyte-secreted protein abundant in the circulation, is implicated in cardiovascular protective functions. Recent work documented that Adipo locally associates with responsive tissues through interactions with T-cadherin (Tcad), an atypical, glycosylphosphatidylinositol (GPI)-anchored cadherin cell surface glycoprotein. Mice deficient for Tcad lack tissue-associated Adipo, accumulate Adipo in the circulation, and mimic the Adipo knockout (KO) cardiovascular phenotype. In reverse, Tcad protein is visibly reduced from cardiac tissue in Adipo-KO mice, suggesting interdependent regulation of the 2 proteins. Here, we evaluate the effect of Adipo on Tcad protein expression. Adipo and Tcad proteins were colocalized in aorta, heart, and skeletal muscle. Adipo positively regulated levels of Tcad protein in vivo and in endothelial cell (EC) cultures. In Tcad-KO mice, binding of endogenous and exogenously administered Adipo to cardiovascular tissues was dramatically reduced. Consistently, knockdown of Tcad in cultured murine vascular ECs significantly diminished Adipo binding. In search for a possible mechanism, we found that enzymatic cleavage of Tcad with phosphatidylinositol-specific phospholipase C increases plasma Adipo while decreasing tissue-bound levels. Similarly, pretreatment of cultured ECs with serum containing Adipo attenuated phosphatidylinositol-specific phospholipase C-mediated Tcad cleavage. In vivo administration of adenovirus producing Adipo suppressed plasma levels of GPI phospholipase D, the endogenous cleavage enzyme for GPI-anchored proteins. In conclusion, our data show that both circulating and tissue-bound Adipo levels are dependent on Tcad and, in reverse, regulate tissue Tcad levels through a positive feedback loop that operates by suppressing phospholipase-mediated Tcad release from the cell surface.
  • Shiro Fukuda; Ayumu Hirata; Hitoshi Nishizawa; Hirofumi Nagao; Susumu Kashine; Takekazu Kimura; Kana Inoue; Yuya Fujishima; Masaya Yamaoka; Junji Kozawa; Tetsuhiro Kitamura; Tetsuyuki Yasuda; Norikazu Maeda; Akihisa Imagawa; Tohru Funahashi; Iichiro Shimomura
    CARDIOVASCULAR DIABETOLOGY 14 2015年01月 [査読有り]
     
    Background: Visceral fat accumulation is a major etiological factor in the progression of type 2 diabetes mellitus and atherosclerosis. We described previously visceral fat accumulation and multiple cardiovascular risk factors in a considerable number of Japanese non-obese subjects (BMI <25 kg/m(2)). Here, we investigated differences in systemic arteriosclerosis, serum adiponectin concentration, and eating behavior in type 2 diabetic patients with and without visceral fat accumulation. Methods: The study subjects were 75 Japanese type 2 diabetes mellitus (age: 64.8 +/- 11.5 years, mean +/- SD). Visceral fat accumulation represented an estimated visceral fat area of 100 cm(2) using the bioelectrical impedance analysis method. Subjects were divided into two groups; with (n = 53) and without (n = 22) visceral fat accumulation. Systemic arteriosclerosis was scored for four arteries by ultrasonography. Eating behavior was assessed based on The Guideline for Obesity questionnaire issued by the Japan Society for the Study of Obesity. Results: The visceral fat accumulation (+) group showed significantly higher systemic vascular scores and significantly lower serum adiponectin levels than the visceral fat accumulation (-) group. With respect to the eating behavior questionnaire items, (+) patients showed higher values for the total score and many of the major sub-scores than (-) patients. Conclusions: Type 2 diabetic patients with visceral fat accumulation showed 1) progression of systemic arteriosclerosis, 2) low serum adiponectin levels, and 3) differences in eating behavior, compared to those without visceral fat accumulation. Taken together, the findings highlight the importance of evaluating visceral fat area in type 2 diabetic patients. Furthermore, those with visceral fat accumulation might need to undergo more intensive screening for systemic arteriosclerosis and consider modifying their eating behaviors.
  • Sokichi Kamata; Shigeru Miyagawa; Satsuki Fukushima; Yukiko Imanishi; Atsuhiro Saito; Norikazu Maeda; Iichiro Shimomura; Yoshiki Sawa
    CIRCULATION JOURNAL 79 1 169 - U437 2015年01月 [査読有り]
     
    Background: Clinical prognosis is critically poor in fulminant myocarditis, while it's initiation or progression is fated, in part, by T cell-mediated autoimmunity. Adiponectin (APN) and associated adipokines were shown to be immune tolerance inducers, although the clinically relevant delivery method into target pathologies is under debate. Whether the cell sheet-based delivery system of adipokines might induce immune tolerance and functional recovery in experimental autoimmune myocarditis (EAM) was tested. Methods and Results: Scaffold-free-induced adipocyte cell-sheet (iACS) was generated by differentiating adipose tissue-derived syngeneic stromal vascular-fraction cells into adipocytes on temperature-responsive dishes. Rats with EAM underwent iACS implantation or sham operation. Supernatants of iACS contained a high level of APN and hepatocyte growth factor (HGF), and reduced proliferation of CD4-positive T cells in vitro. Immunohistolabelling showed that the iACS implantation elevated the levels of APN and HGF in the myocardium compared to the sham operation, which attenuated the immunological response by inhibiting CD68-positive macropharges and CD4-positive T-cells and activating Foxp3-positive regulatory T cells. Consequently, left ventricular ejection fraction was significantly greater after the iACS implantation than after the sham operation, in association with less collagen accumulation. Conclusions: The targeted delivery of adipokines using tissue-engineered iACS ameliorated cardiac performance of the EAM rat model via effector T cell suppression and induction of immune tolerance. These findings might suggest a potential of this tissue-engineered drug delivery system in treating fulminant myocarditis in the clinical setting.
  • Masaya Yamaoka; Norikazu Maeda; Yasunori Takayama; Ryohei Sekimoto; Yu Tsushima; Keisuke Matsuda; Takuya Mori; Kana Inoue; Hitoshi Nishizawa; Makoto Tominaga; Tohru Funahashi; Iichiro Shimomura
    PLOS ONE 9 11 2014年11月 [査読有り]
     
    Visceral fat adiposity plays an important role in the development of metabolic syndrome. We reported previously the impact of human visceral fat adiposity on gene expression profile of peripheral blood cells. Genes related to circadian rhythm were highly associated with visceral fat area and period homolog 1 (PER1) showed the most significant negative correlation with visceral fat area. However, regulation of adipose Per1 remains poorly understood. The present study was designed to understand the regulation of Per1 in adipose tissues. Adipose Per1 mRNA levels of ob/ob mice were markedly low at 25 and 35 weeks of age. The levels of other core clock genes of white adipose tissues were also low in ob/ob mice at 25 and 35 weeks of age. Per1 mRNA was mainly expressed in the mature adipocyte fraction (MAF) and it was significantly low in MAF of ob/ob mice. To examine the possible mechanisms, 3T3-L1 adipocytes were treated with H2O2, tumor necrosis factor-alpha (TNF-alpha), S100A8, and lipopolysaccharide (LPS). However, no significant changes in Per1 mRNA level were observed by these agents. Exposure of cultured 3T3-L1 adipocytes to low temperature (33 degrees C) decreased Per1 and catalase, and increased monocyte chemoattractant protein-1 (Mcp-1) mRNA levels. Hypothermia also worsened insulin-mediated Akt phosphorylation in 3T3-L1 adipocytes. Finally, telemetric analysis showed low temperature of adipose tissues in ob/ob mice. In obesity, adipose hypothermia seems to accelerate adipocyte dysfunction.
  • Kana Inoue; Norikazu Maeda; Yuya Fujishima; Shiro Fukuda; Hirofumi Nagao; Masaya Yamaoka; Ayumu Hirata; Hitoshi Nishizawa; Tohru Funahashi; Iichiro Shimomura
    DIABETOLOGY & METABOLIC SYNDROME 6 2014年09月 [査読有り]
     
    Background: Liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, has been shown to possess pleiotropic effects including body weight reduction. However, long-term effect of liraglutide on body weight and glycemic control has not been elucidated in Japanese type 2 diabetes (T2D) subjects. Present study investigates whether liraglutide treatment maintains the body weight-decreasing and glucose-lowering effects for 2 years in Japanese T2D subjects. Methods: The enrolled subjects were 86 T2D patients [age; 59.8 +/- 12.8 years, duration of diabetes; 15.8 +/- 9.5 years, glycated hemoglobin (HbA1c); 8.5 +/- 1.5%, body mass index (BMI); 27.3 +/- 5.4 kg/m(2) (15.8 -46.5 kg/m(2)), mean +/- SD]. Among 86 subjects, liraglutide was introduced in 25 inpatients and 61 outpatients, and 46 subjects were followed for 2 years. Clinical parameters were measured at baseline and 3, 6, 9, 12, and 24 months after liraglutide introduction. The increase in liraglutide dosage and the additional usage of glucose-lowering agents depended on each attending physician. Results: At 1 year after liraglutide introduction, 69 patients (80.2%) decreased body weight and 58 patients (67.4%) improved glycemic control. Body mass index (BMI) was changed 27.3 +/- 5.4 kg/m(2) to 25.9 +/- 4.8 kg/m(2) and percent reduction of body weight was significant and maintained over 4% at 2 years after liraglutide introduction. HbA1c was significantly decreased from 8.5 +/- 1.5% to 7.7 +/- 1.2% for 2 years. Liraglutide treatment tended to ameliorate lipid profile and hepatic enzymes. Stepwise regression analysis demonstrated that baseline BMI and previous insulin dose were positively associated with body weight reduction and baseline HbA1c was positively associated with reduction of HbA1c at 2 years after liraglutide introduction. Conclusions: Long-term liraglutide treatment effectively maintained the reduction of body weight and the fair glycemic control, and also improved lipid profile and liver enzymes in Japanese T2D subjects.
  • Takuya Mori; Yoshihisa Koyama; Norikazu Maeda; Yukiko Nakamura; Yuya Fujishima; Keisuke Matsuda; Tohru Funahashi; Shoichi Shimada; Iichiro Shimomura
    SCIENTIFIC REPORTS 4 2014年05月 [査読有り]
     
    Adiponectin, adipose-specific secretory protein, abundantly circulates in bloodstream and its concentration is around 1000-fold higher than that of other cytokines and hormones. Hypoadiponectinemia is a risk factor for atherosclerosis. There is little or no information on ultrastructural localization of adiponectin in the vasculature. Herein we investigated the localization of vascular adiponectin in the aorta using the immunoelectron microscopic technique. In wild-type (WT) mice, adiponectin was mainly detected on the luminal surface membrane of endothelial cells (ECs) and also found intracellularly in the endocytic vesicles of ECs. In the atherosclerotic lesions of apolipoprotein E-knockout (ApoE-KO) mice, adiponectin was detected in ECs, on the cell surface membrane of synthetic smooth muscle cells, and on the surface of monocytes adherent to ECs. Changes in adiponectin localization within the wall of the aorta may provide novel insight into the pathogenesis of atherosclerosis.
  • Toshiyuki Hibuse; Norikazu Maeda; Ken Kishida; Takekazu Kimura; Tomoko Minami; Eriko Takeshita; Ayumu Hirata; Yasuhiko Nakagawa; Susumu Kashine; Akemi Oka; Masumi Hayashi; Hitoshi Nishizawa; Tohru Funahashi; Iichiro Shimomura
    CARDIOVASCULAR DIABETOLOGY 13 2014年05月 [査読有り]
     
    Background: The dipeptidyl-peptidase-IV (DPP-4) inhibitors, including sitagliptin, are used for the treatment of type 2 diabetes mellitus (T2DM). Adiponectin, an adipocyte-derived circulating protein, has anti-atherosclerotic and anti-diabetic properties and is effectively elevated in bloodstream by thiazolidinediones, an insulin sensitizer. However, the effect of sitagliptin treatment on serum adiponectin level in T2DM has not fully elucidated in Japanese T2DM patients. The aim of the present study was to examine the effect of sitagliptin treatment on serum adiponectin levels in T2DM subjects. Methods: Twenty-six consecutive Japanese T2DM outpatients were recruited between April 2011 and March 2013, and randomized into the control (conventional treatment, n = 10) group and sitagliptin treatment group (n = 16). Serum adiponectin was measured by enzyme-linked immunosorbent assay. Results: Indices of glycemic control, such as hemoglobin A1c, glycated albumin, and 1.5-anhydro-D-glucitol, were significantly improved after the three-month treatment in both the control and sitagliptin groups. Serum adiponectin level was significantly increased in sitagliptin group from 6.7 +/- 0.8 to 7.4 +/- 1.0 mu g/mL without change of body mass index (p = 0.034), while serum adiponectin level was not altered in the control group (p = 0.601). Conclusion: In Japanese T2DM patients, serum adiponectin level was elevated by three-month treatment with sitagliptin without change of body weight.
  • Fujishima Y; Maeda N; Matsuda K; Komura N; Hirata A; Mori T; Sekimoto R; Tsushima Y; Nishizawa H; Funahashi T; Shimomura I
    Biochem Biophys Res Commun. 444 2 224 - 229 2014年02月 [査読有り]
     
    Obesity is associated with heart failure and cardiac hypertrophy. Adiponectin has been shown to play a protective role for cardiovascular diseases. The beta-catenin signaling pathway is deeply involved in cardiac hypertrophy. However, the effect of adiponectin on beta-catenin signaling has not been investigated in cardiac hypertrophy. Present study aimed to clarify the involvement of adiponectin and beta-catenin signaling pathway in the mouse model of angiotensin II (AngII)-induced cardiac hypertrophy. In hearts of Wild type (WT) mice, AngII dose-dependently augmented cytosolic beta-catenin protein level. WT and adiponectin knockout (Adipo-KO) mice were administered with AngII at 2.4 mg/kg/day for 14 days and were also injected with adenovirus expressing the adiponectin (Ad-Adipo) or the beta-galactosidase (Ad-beta gal). Cardiac mRNA levels relating to hypertrophy and beta-catenin signaling were increased in Adipo-KO mice and these changes were reversed by Ad-Adipo. Phosphorylation of Akt was increased in Adipo-KO mice and such increases were reversed by Ad-Adipo. Furthermore, the phosphorylation of glycogen synthase kinase 313 (GSK313) at Ser(9) and cytosolic beta-catenin level were increased in Adipo-KO mice and they were significantly reduced by Ad-Adipo treatment. Phosphorylation of mammalian target of rapamycin (mTOR) was reduced by Ad-Adipo-mediated adiponectin supplementation in WT and Adipo-KO mice. The current study suggests that adiponectin attenuates AngII-induced cardiac hypertrophic signals partly through Akt/GSK3 beta/beta-catenin and Akt/mTOR pathways. (C) 2014 Elsevier Inc. All rights reserved.
  • Kana Inoue; Norikazu Maeda; Takuya Mori; Ryohei Sekimoto; Yu Tsushima; Keisuke Matsuda; Masaya Yamaoka; Takayoshi Suganami; Hitoshi Nishizawa; Yoshihiro Ogawa; Tohru Funahashi; Iichiro Shimomura
    PLOS ONE 9 2 2014年02月 [査読有り]
     
    Obesity is an epidemic matter increasing risk for cardiovascular diseases and metabolic disorders such as type 2 diabetes. We recently examined the association between visceral fat adiposity and gene expression profile of peripheral blood cells in human subjects. In a series of studies, Opa (Neisseria gonorrhoeae opacity-associated)-interacting protein 5 (OIP5) was nominated as a molecule of unknown function in adipocytes and thus the present study was performed to investigate the role of OIP5 in obesity. Adenovirus overexpressing Oip5 (Ad-Oip5) was generated and infected to 3T3-L1 cells stably expressing Coxsackie-Adenovirus Receptor (CAR-3T3-L1) and to mouse subcutaneous fat. For a knockdown experiment, siRNA against Oip5 (Oip5-siRNA) was introduced into 3T3-L1 cells. Proliferation of adipose cells was measured by BrdU uptake, EdU-staining, and cell count. Significant increase of Oip5 mRNA level was observed in obese white adipose tissues and such increase was detected in both mature adipocytes fraction and stromal vascular cell fraction. Ad-Oip5-infected CAR-3T3-L1 preadipocytes and adipocytes proliferated rapidly, while a significant reduction of proliferation was observed in Oip5-siRNA-introduced 3T3-L1 preadipocytes. Fat weight and number of adipocytes were significantly increased in Ad-Oip5-administered fat tissues. Oip5 promotes proliferation of pre- and mature-adipocytes and contributes adipose hyperplasia. Increase of Oip5 may associate with development of obesity.
  • Hanaoka Y; Yasuda O; Soejima H; Miyata K; Yamamoto E; Izumiya Y; Maeda N; Ohishi M; Rakugi H; Oike Y; Kim-Mitsuyama S; Ogawa H
    PloS one 9 4 e94930  2014年 [査読有り]
     
    Tissue inhibitors of metalloproteinases (TIMPs) regulate matrix metalloproteinase activity and maintain extracellular matrix homeostasis. Although TIMP-3 has multiple functions (e.g., apoptosis, inhibition of VEGF binding to VEGF receptor, and inhibition of TNFα converting enzyme), its roles in thermogenesis and metabolism, which influence energy expenditure and can lead to the development of metabolic disorders when dysregulated, are poorly understood. This study aimed to determine whether TIMP-3 is implicated in metabolism by analyzing TIMP-3 knockout (KO) mice. TIMP-3 KO mice had higher body temperature, oxygen consumption, and carbon dioxide production than wild-type (WT) mice, although there were no differences in food intake and locomotor activity. These results suggest that metabolism is enhanced in TIMP-3 KO mice. Real-time PCR analysis showed that the expression of PPAR-δ, UCP-2, NRF-1 and NRF-2 in soleus muscle, and PGC-1α and UCP-2 in gastrocnemius muscle, was higher in TIMP-3 KO mice than in WT mice, suggesting that TIMP-3 deficiency may increase mitochondrial activity. When exposed to cold for 8 hours to induce thermogenesis, TIMP-3 KO mice had a higher body temperature than WT mice. In the treadmill test, oxygen consumption and carbon dioxide production were higher in TIMP-3 KO mice both before and after starting exercise, and the difference was more pronounced after starting exercise. Our findings suggest that TIMP-3 KO mice exhibit enhanced metabolism, as reflected by a higher body temperature than WT mice, possibly due to increased mitochondrial activity. Given that TIMP-3 deficiency increases energy expenditure, TIMP-3 may present a novel therapeutic target for preventing metabolic disorders.
  • Satoshi Tetsumoto; Yoshito Takeda; Hirohiko Imai; Atsuomi Kimura; Yingji Jin; Kaori Nakanishi; Yohei Maeda; Hanako Kuhara; Kazuyuki Tsujino; Takeo Iwasaki; Hiroshi Shigeta; Yasushi Kondo; Mari Ito; Toshiyuki Minami; Haruhiko Hirata; Ryo Takahashi; Satoshi Kohmo; Izumi Nagatomo; Koji Inoue; Hiroshi Kida; Takashi Kijima; Isao Tachibana; Norikazu Maeda; Toru Funahashi; Iichiro Shimomura; Hideaki Fujiwara; Atsushi Kumanogoh
    AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY 49 4 592 - 600 2013年10月 [査読有り]
     
    Animal disease models are pivotal in investigating the pathogenesis of emphysema and developing novel drugs, but the modalities to evaluate murine emphysema models have been of limited validity and sensitivity. In this study, we evaluated hyperpolarized Xe-129 magnetic resonance imaging (MRI) and micro-computed tomography (micro-CT) compared with traditional methods, such as plethysmography and histology. Elastase-treated mice and adiponectin knockout mice were used as murine emphysema models to evaluate these modalities. Three weeks after elastase administration, significant and heterogeneous emphysema was evaluated according to the mean linear intercept and plethysmography parameters. Notably, the distribution of low-density areas, as examined by micro-CT, correlated with the mean linear intercept and plethysmography parameters in whole lungs. These correlations were also observed in regional areas. Furthermore, we introduced hyperpolarized Xe-129 MRI, which can evaluate gas exchange between the alveoli and blood during spontaneous breathing. Parameters of gas exchange (fD) and alveolar size (Vs/Va) were significantly decreased in elastase-treated mice, and moderately correlated with the plethysmography parameters. Of importance, we could detect a decrease of the fD value in low-density areas with micro-CT, suggesting that gas exchange decreased in emphysematous lesions. Likewise, these parameters (fD and Vs/Va) were also decreased in adiponectin knockout mice, which exhibit emphysema with a homogeneous distribution. We demonstrated the feasibility of Xe-129 MRI and micro-CT in combination with traditional modalities. These noninvasive modalities provide complementary data that can be used for repeated estimations of regional gas exchange and lung morphology.
  • Takuya Mori; Norikazu Maeda; Kana Inoue; Ryohei Sekimoto; Yu Tsushima; Keisuke Matsuda; Masaya Yamaoka; Takayoshi Suganami; Hitoshi Nishizawa; Yoshihiro Ogawa; Tohru Funahashi; Iichiro Shimomura
    PLOS ONE 8 10 2013年10月 [査読有り]
     
    Aims: Ephrin-B1 (EfnB1) was selected among genes of unknown function in adipocytes or adipose tissue and subjected to thorough analysis to understand its role in the development of obesity. Methods and Results: EfnB1 mRNA and protein levels were significantly decreased in adipose tissues of obese mice and such reduction was mainly observed in mature adipocytes. Exposure of 3T3-L1 adipocytes to tumor necrosis factor-alpha (TNF-alpha) and their culture with RAW264.7 cells reduced EFNB1 levels. Knockdown of adipose EFNB1 increased monocyte chemoattractant protein-1 (Mcp-1) mRNA level and augmented the TNF-alpha-mediated THP-1 monocyte adhesion to adipocytes. Adenovirus-mediated adipose EFNB1-overexpression significantly reduced the increase in Mcp-1 mRNA level induced by coculture of 3T3-L1 adipocytes with RAW264.7 cells. Monocyte adherent assay showed that adipose EfnB1-overexpression significantly decreased the increase of monocyte adhesion by coculture with RAW264.7 cells. TNF-alpha-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) was reduced by EFNB1-overexpression. Conclusions: EFNB1 contributes to the suppression of adipose inflammatory response. In obesity, reduction of adipose EFNB1 may accelerate the vicious cycle involved in adipose tissue inflammation.
  • Yu Tsushima; Hitoshi Nishizawa; Yoshihiro Tochino; Hideaki Nakatsuji; Ryohei Sekimoto; Hirofumi Nagao; Takashi Shirakura; Kenta Kato; Keiichiro Imaizumi; Hiroyuki Takahashi; Mizuho Tamura; Norikazu Maeda; Tohru Funahashi; Iichiro Shimomura
    JOURNAL OF BIOLOGICAL CHEMISTRY 288 38 27138 - 27149 2013年09月 [査読有り]
     
    Obesity is often accompanied by hyperuricemia. However, purine metabolism in various tissues, especially regarding uric acid production, has not been fully elucidated. Here we report, using mouse models, that adipose tissue could produce and secrete uric acid through xanthine oxidoreductase (XOR) and that the production was enhanced in obesity. Plasma uric acid was elevated in obese mice and attenuated by administration of the XOR inhibitor febuxostat. Adipose tissue was one of major organs that had abundant expression and activities of XOR, and adipose tissues in obese mice had higher XOR activities than those in control mice. 3T3-L1 and mouse primary mature adipocytes produced and secreted uric acid into culture medium. The secretion was inhibited by febuxostat in a dose-dependent manner or by gene knockdown of XOR. Surgical ischemia in adipose tissue increased local uric acid production and secretion via XOR, with a subsequent increase in circulating uric acid levels. Uric acid secretion from whole adipose tissue was increased in obese mice, and uric acid secretion from 3T3-L1 adipocytes was increased under hypoxia. Our results suggest that purine catabolism in adipose tissue could be enhanced in obesity.
  • Noriyuki Komura; Norikazu Maeda; Takuya Mori; Shinji Kihara; Hideaki Nakatsuji; Ayumu Hirata; Yoshihiro Tochino; Tohru Funahashi; Iichiro Shimomura
    PLOS ONE 8 8 2013年08月 [査読有り]
     
    Aims: Inflammation is closely associated with the development of atherosclerosis and metabolic syndrome. Adiponectin, an adipose-derived secretory protein, possesses an anti-atherosclerotic property. The present study was undertaken to elucidate the presence and significance of adiponectin in vasculature. Methods and Results: Immunofluorescence staining was performed in aorta of wild-type (WT) mice and demonstrated that adiponectin was co-stained with CD31. Thoracic aorta was cut through and then aortic intima was carefully shaved from aorta. Western blotting showed the existence of adiponectin protein in aortic intima, while there was no adiponectin mRNA expression. Adiponectin knockout (Adipo-KO) and WT mice were administered with a low-dose and short-term lipopolysaccharide (LPS) (1 mg/kg of LPS for 4 hours). The endothelium vascular adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) were highly increased in Adipo-KO mice compared to WT mice after LPS administration. Conclusions: Adiponectin protein exists in aortic endothelium under steady state and may protect vasculature from the initiation of atherosclerosis.
  • Hirofumi Nagao; Susumu Kashine; Hitoshi Nishizawa; Takuya Okada; Takekazu Kimura; Ayumu Hirata; Shiro Fukuda; Junji Kozawa; Norikazu Maeda; Tetsuhiro Kitamura; Tetsuyuki Yasuda; Kohei Okita; Toshiyuki Hibuse; Mamiko Tsugawa; Akihisa Imagawa; Tohru Funahashi; Iichiro Shimomura
    CARDIOVASCULAR DIABETOLOGY 12 2013年06月 [査読有り]
     
    Background: Although many Asian type 2 diabetic patients have been considered to be not obese and have low capacity of insulin secretion, the proportion of obese patients with visceral fat accumulation has increased in recent years. We found previously considerable number of Japanese non-obese subjects (body mass index (BMI) < 25 kg/m(2)) with visceral fat accumulation and multiple cardiovascular risk factors. The aim of the study was to investigate the difference in clinical features of type 2 diabetic patients with and without visceral fat accumulation, focusing on vascular complications and changes in BMI. Methods: We enrolled 88 Japanese hospitalized type 2 diabetic patients. Abdominal obesity represented waist circumference (WC) of >= 85 cm for males and >= 90 cm for females (corresponding to visceral fat area of 100 cm(2)). Subjects were divided into two groups; with or without abdominal obesity. Results: Hypertension, dyslipidemia and cardiovascular diseases were significantly more in the patients with abdominal obesity. The prevalence of cardiovascular disease in the non-obese patients (BMI < 25 kg/m(2)) with abdominal obesity were similar in obese patients (BMI >= 25 kg/m(2)). The mean BMI of the patients with abdominal obesity was < 25 kg/m(2) at 20 years of age, but reached maximum to more than 30 kg/m(2) in the course. Furthermore, substantial portion of the type 2 diabetic patients (52% in males and 43% in females) were not obese at 20 year-old (BMI < 25 kg/m(2)), but developed abdominal obesity by the time of admission. Conclusion: These results emphasize the need to control multiple risk factors and prevent atherosclerotic disease in patients with abdominal obesity. The significant weight gain after 20 years of age in patients with abdominal obesity stresses the importance of lifestyle modification in younger generation, to prevent potential development of type 2 diabetes and future atherosclerotic cardiovascular disease.
  • Masaya Yamaoka; Norikazu Maeda; Seiji Nakamura; Takuya Mori; Kana Inoue; Keisuke Matsuda; Ryohei Sekimoto; Susumu Kashine; Yasuhiko Nakagawa; Yu Tsushima; Yuya Fujishima; Noriyuki Komura; Ayumu Hirata; Hitoshi Nishizawa; Yuji Matsuzawa; Ken-ichi Matsubara; Tohru Funahashi; Iichiro Shimomura
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 433 4 450 - 455 2013年04月 [査読有り]
     
    Objective: Visceral fat obesity is located upstream of metabolic syndrome and atherosclerotic diseases. Accumulating evidences indicate that several immunocytes including macrophages infiltrate into adipose tissue and induce chronic low-grade inflammation. We recently analyzed the association between visceral fat adiposity and the gene expression profile in peripheral blood cells in human subjects and demonstrated the close relationship of visceral fat adiposity and disturbance of circadian rhythm in peripheral blood cells. In a series of studies, we herein investigated the association of visceral fat adiposity and mRNA levels relating to inflammatory genes in peripheral blood cells. Approach and Results: Microarray analysis was performed in peripheral blood cells from 28 obese subjects. Reverse transcription-polymerase chain reaction (RT-PCR) was conducted by using blood cells from 57 obese subjects. Obesity was defined as body mass index (BMI) greater than 25 kg/m(2) according to the Japanese criteria. Gene expression profile analysis was carried out with Agilent whole human genome 4 x 44K oligo-DNA microarray. Gene ontology (GO) analysis showed that 14 genes were significantly associated with visceral fat adiposity among 239 genes relating to inflammation. Among 14 genes, RT-PCR demonstrated that S100A8, S100A9, and S100A12 positively correlated with visceral fat adiposity in 57 subjects. Stepwise multiple regression analysis showed that S100A8 and S100A12 mRNA levels were closely associated with HOMA-IR and S100A9 mRNA was significantly related to adiponectin and CRP. Conclusions: Peripheral blood mRNA levels of S100 family were closely associated with insulin resistance and inflammation. (C) 2013 Elsevier Inc. All rights reserved.
  • Kozawa J; Kitamura T; Nishizawa H; Yasuda T; Maeda N; Otsuki M; Okita K; Iwahashi H; Kaneto H; Funahashi T; Imagawa A; Shimomura I
    Journal of diabetes investigation 4 2 190 - 194 2013年03月 [査読有り]
  • Norikazu Maeda; Tohru Funahashi; Iichiro Shimomura
    ENDOCRINE JOURNAL 60 3 251 - 259 2013年03月 [査読有り][招待有り]
     
    Visceral fat accumulation is located upstream of metabolic syndrome. Recent progress in adipocyte biology has clarified the molecular mechanism for pathophysiology of metabolic syndrome and its related disorders. In this review we summarize adiponectin and aquaporin 7 (AQP7) in the role of metabolic syndrome and cardiovascular diseases.
  • Asuka Shiota; Michio Shimabukuro; Daiju Fukuda; Takeshi Soeki; Hiromi Sato; Etsuko Uematsu; Yoichiro Hirata; Hirotsugu Kurobe; Norikazu Maeda; Hiroshi Sakaue; Hiroaki Masuzaki; Iichiro Shimomura; Masataka Sata
    CARDIOVASCULAR DIABETOLOGY 11 2012年11月 [査読有り]
     
    Background: Telmisartan is a well-established angiotensin II type 1 receptor blocker that improves insulin sensitivity in animal models of obesity and insulin resistance, as well as in humans. Telmisartan has been reported to function as a partial agonist of the peroxisome proliferator-activated receptor (PPAR) gamma, which is also targeted by the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase (SIRT1). Here, we investigated the pathways through which telmisartan acts on skeletal muscle, in vitro as well as in vivo.Methods: Nine-week-old male db/db mice were fed a 60% high-fat diet, with orally administrated either vehicle (carboxymethyl-cellulose, CMC), 5 mg/kg telmisartan, or 5 mg/kg telmisartan and 1 mg/kg GW9662, a selective irreversible antagonist of PPAR gamma, for 5 weeks. Effects of telmisartan on Sirt1 mRNA, AMPK phosphorylation, and NAD +/NADH ratio were determined in C2C12 cultured myocytes.Results and discussion: Telmisartan treatment improved insulin sensitivity in obese db/db mice fed a high-fat diet and led to reduction in the size of hypertrophic pancreatic islets in these mice. Moreover, in vitro treatment with telmisartan led to increased expression of Sirt1 mRNA in C2C12 skeletal muscle cells; the increase in Sirt1 mRNA in telmisartan-treated C2C12 myoblasts occurred concomitantly with an increase in AMPK phosphorylation, an increase in NAD+/NADH ratio, and increases in the mRNA levels of PGC1 alpha, FATP1, ACO, and GLUT4.Conclusions: Our results indicate that telmisartan acts through a PPAR gamma-independent pathway, but at least partially exerts its effects by acting directly on skeletal muscle AMPK/SIRT1 pathways.
  • Masaya Yamaoka; Norikazu Maeda; Seiji Nakamura; Susumu Kashine; Yasuhiko Nakagawa; Aki Hiuge-Shimizu; Kohei Okita; Akihisa Imagawa; Yuji Matsuzawa; Ken-ichi Matsubara; Tohru Funahashi; Iichiro Shimomura
    PLOS ONE 7 10 2012年10月 [査読有り]
     
    Evidence suggests that visceral fat accumulation plays a central role in the development of metabolic syndrome. Excess visceral fat causes local chronic low-grade inflammation and dysregulation of adipocytokines, which contribute in the pathogenesis of the metabolic syndrome. These changes may affect the gene expression in peripheral blood cells. This study for the first time examined the association between visceral fat adiposity and gene expression profile in peripheral blood cells. The gene expression profile was analyzed in peripheral blood cells from 28 obese subjects by microarray analysis. Reverse transcription-polymerase chain reaction (RT-PCR) was performed using peripheral blood cells from 57 obese subjects. Obesity was defined as body mass index (BMI) greater than 25 kg/m(2) according to the Japanese criteria, and the estimated visceral fat area (eVFA) was measured by abdominal bioelectrical impedance. Analysis of gene expression profile was carried out with Agilent whole human genome 4644 K oligo-DNA microarray. The expression of several genes related to circadian rhythm, inflammation, and oxidative stress correlated significantly with visceral fat accumulation. Period homolog 1 (PER1) mRNA level in blood cells correlated negatively with visceral fat adiposity. Stepwise multiple regression analysis identified eVFA as a significant determinant of PER1 expression. In conclusion, visceral fat adiposity correlated with the expression of genes related to circadian rhythm and inflammation in peripheral blood cells.
  • Norikazu Maeda
    MOLECULAR ASPECTS OF MEDICINE 33 5-6 665 - 675 2012年10月 [査読有り][招待有り]
     
    The discovery of water channel protein (aquaporin [AQP]) has made a great impact on life sciences. So far, 13 AQPs have been identified in human. AQP3, 7, 9, and 10 are subcategorized as aquaglyceroporins which permeabilize glycerol as well as water. Many investigators have demonstrated that AQPs play a crucial role in the maintenance of water homeostasis, but the physiological significance of some AQPs as glycerol channels remains elusive. Adipocyte is a major source of glycerol, which is one of the substrates for hepatic gluconeogenesis. This review focuses on recent studies on glycerol metabolism through AQP7 and AQP9, and briefly discusses the importance of glycerol channel in adipocytes, liver, and heart. (C) 2012 Elsevier Ltd. All rights reserved.
  • Yuya Fujishima; Norikazu Maeda; Kana Inoue; Susumu Kashine; Hitoshi Nishizawa; Ayumu Hirata; Junji Kozawa; Tetsuyuki Yasuda; Kohei Okita; Akihisa Imagawa; Tohru Funahashi; Iichiro Shimomura
    CARDIOVASCULAR DIABETOLOGY 11 2012年09月 [査読有り]
     
    Background: We recently reported that short-term treatment with liraglutide (20.0 +/- 6.4 days) reduced body weight and improved some scales of eating behavior in Japanese type 2 diabetes inpatients. However, it remained uncertain whether such liraglutide-induced improvement is maintained after discharge from the hospital. The aim of the present study was to determine the long-term effects of liraglutide on body weight, glycemic control, and eating behavior in Japanese obese type 2 diabetics. Methods: Patients with obesity (body mass index (BMI) >25 kg/m(2)) and type 2 diabetes were hospitalized at Osaka University Hospital between November 2010 and December 2011. BMI and glycated hemoglobin (HbA1c) were examined on admission, at discharge and at 1, 3, and 6 months after discharge. For the liraglutide group (BMI; 31.3 +/- 5.3 kg/m(2), n = 29), patients were introduced to liraglutide after correction of hyperglycemic by insulin or oral glucose-lowering drugs and maintained on liraglutide after discharge. Eating behavior was assessed in patients treated with liraglutide using The Guideline For Obesity questionnaire issued by the Japan Society for the Study of Obesity, at admission, discharge, 3 and 6 months after discharge. For the insulin group (BMI; 29.1 +/- 3.0 kg/m(2), n = 28), each patient was treated with insulin during hospitalization and glycemic control maintained by insulin after discharge. Results: Liraglutide induced significant and persistent weight loss from admission up to 6 months after discharge, while no change in body weight after discharge was noted in the insulin group. Liraglutide produced significant improvements in all major scores of eating behavior questionnaire items and such effect was maintained at 6 months after discharge. Weight loss correlated significantly with the decrease in scores for recognition of weight and constitution, sense of hunger, and eating style. Conclusion: Liraglutide produced meaningful long-term weight loss and significantly improved eating behavior in obese Japanese patients with type 2 diabetes.
  • Junji Kozawa; Kana Inoue; Ryuya Iwamoto; Yukiko Kurashiki; Yukiyoshi Okauchi; Susumu Kashine; Tetsuhiro Kitamura; Norikazu Maeda; Kohei Okita; Hiromi Iwahashi; Tohru Funahashi; Akihisa Imagawa; Iichiro Shimomura
    JOURNAL OF DIABETES INVESTIGATION 3 3 294 - 297 2012年06月 [査読有り]
     
    Aims/Introduction: Recently, glucagon-like peptide-1 (GLP-1) receptor agonists of liraglutide have become available in Japan. It has not yet been clarified what clinical parameters could discriminate liraglutide-effective patients from liraglutide-ineffective patients. Materials and Methods: We reviewed 23 consecutive patients with type 2 diabetes admitted to Osaka University Hospital for glycemic control. All of the patients were treated with diet plus insulin (or plus oral antidiabetic drugs) to improve fasting plasma glucose (FPG) and postprandial glucose below 150 and 200 mg/dL, respectively. After insulin secretion and insulin resistance were evaluated, insulin was replaced by liraglutide. The efficacy of liraglutide was determined according to whether glycemic control was maintained at the target levels. Results: Liraglutide was effective in 13 of 23 patients. There were significant differences in the parameters of insulin secretion, including fasting C-peptide (F-CPR), C-peptide index (CPI), insulinogenic index (I.I.) and urine C-peptide (U-CPR), between liraglutide-effective and -ineffective patients. The duration of diabetes was significantly shorter in liraglutide-effective patients than in liraglutide-ineffective patients. In receiver operating characteristic analyses, the cut-off value for predicting the efficacy of liraglutide was 0.14 for I.I., 1.1 for CPI, 1.5 ng/mL for F-CPR, 33.3 mu g/day for U-CPR and 19.5 years for duration of type 2 diabetes. Conclusions: Insulin secretion evaluated by F-CPR, CPI, I.I., U-CPR and the duration of type 2 diabetes were useful parameters for predicting the efficacy of liraglutide in patients with type 2 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00168.x, 2011)
  • Maeda N; Shimomura I
    Nihon rinsho. Japanese journal of clinical medicine 70 Suppl 3 486 - 489 2012年05月 [査読有り]
  • Matijs van Meurs; Pedro Castro; Nathan I. Shapiro; Shulin Lu; Midori Yano; Norikazu Maeda; Tohru Funahashi; Ichiro Shimomura; Jan G. Zijlstra; Grietje Molema; Samir M. Parikh; William C. Aird; Kiichiro Yano
    SHOCK 37 4 392 - 398 2012年04月 [査読有り]
     
    Experimental sepsis was induced in male C57BL/6j, adiponectin-deficient mice (ADPNKO), and wild-type littermates by i.p. injection of 16 mg/kg lipopolysaccharide or cecal ligation and puncture. Blood and tissue samples were harvested 24 h after model induction. Circulating adiponectin is reduced in mice with endotoxemic challenge and after cecal ligation and puncture compared with healthy control mice. Quantitative reverse transcriptase-polymerase chain reaction for adiponectin reveals a pattern of response that is both model-and organ-specific. When challenged with sepsis, adiponectin deficiency results in increased expression of endothelial adhesion and coagulation molecules in the lung, liver, and kidney as quantified by reverse transcriptase-polymerase chain reaction, increased macrophage and neutrophil infiltration by immunohistochemistry, and vascular leakage in the liver and kidney. Adiponectin-deficient mice have reduced survival following cecal ligation and puncture and increased blood levels of interleukin 6, soluble vascular endothelial growth factor receptor 1, and soluble endothelial adhesion molecules E-selectin and intercellular adhesion molecule 1. Finally, ADPNKO promoted end-organ injury in the liver and kidney, whereas the lungs were not affected. These data suggest a protective role of adiponectin in diminishing microvascular organ-specific endothelial cell activation during sepsis.
  • Ayumu Hirata; Norikazu Maeda; Hideaki Nakatsuji; Aki Hiuge-Shimizu; Takuya Okada; Tohru Funahashi; Iichiro Shimomura
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 419 2 182 - 187 2012年03月 [査読有り]
     
    Aims: Mineralocorticoid receptor (MR) blockade ameliorated insulin resistance with improvements in adipocytokine dysregulation, inflammation, and excess of reactive oxygen species (ROS) in obese adipose tissue and adipocytes, but its mechanism has not been clarified. The 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1), producing active glucocorticoids, is highly expressed in adipocytes and glucocorticoids bind to MR with higher affinity than to glucocorticoid receptor (GR). We investigated whether glucocorticoids effect on adipocytokines and ROS through MR in adipocytes. In addition, fat distributions of MR and GR were investigated in human subjects. Methods and Results: Corticoid receptors and their target genes were examined in adipose tissue of obese db/db mice. 3T3-L1 adipocytes were treated with glucocorticoids, H2O2, MR antagonist eplerenone (EP), GR antagonist RU486 (RU), MR-siRNA, and/or N-acetylcysteine. Human adipose tissues were obtained from seven patients who underwent abdominal surgery. The mRNA levels of MR and its target gene were higher in db/db mice than in control db/m + mice. In 3T3-L1 adipocytes, glucocorticoids, similar to H2O2, caused the dysregulation of mRNA levels of various genes related to adipocytokines and the increase of intracellular ROS. Such changes were rectified by MR blockade, not by GR antagonist. In human fat, MR mRNA level was increased in parallel with the increase of body mass index (BMI) and its increase was more significant in visceral fat, while there were no apparent correlations of GR mRNA level to BMI or fat distribution. Conclusion: Glucocorticoid-MR pathway may contribute to the obesity-related adipocytokine dysregulation and adipose ROS. (C) 2012 Elsevier Inc. All rights reserved.
  • Naoto Katakami; Hideaki Kaneto; Taka-aki Matsuoka; Mitsuyoshi Takahara; Norikazu Maeda; Ikki Shimizu; Keizo Ohno; Takeshi Osonoi; Koichi Kawai; Fukashi Ishibashi; Kenichi Imamura; Atsunori Kashiwagi; Ryuzo Kawamori; Munehide Matsuhisa; Tohru Funahashi; Yoshimitsu Yamasaki; Iichiro Shimomura
    ATHEROSCLEROSIS 220 2 437 - 442 2012年02月 [査読有り]
     
    Objective: Adiponectin has anti-atherogenic properties and reduced serum adiponectin levels are associated with cardiovascular disease (CVD). In this study, we examined the relationship between CVD and adiponectin (ADIPOQ) gene G276T polymorphism that is associated with serum adiponectin level in a large cohort of type 2 diabetic patients. Research design and methods: We enrolled 2637 Japanese type 2 diabetic subjects (males, 61.1%; age, 54.9 +/- 7.9 years old), determined their genotypes regarding ADIPOQ G276T polymorphisms, and evaluated the association between this polymorphism and the prevalence of CVD (myocardial infarction and/or cerebral infarction). Results: The prevalence of CVD tended to be higher as the number of G alleles increased [GG (9.5%), GT (6.8%), TT (5.6%), p value for trend = 0.0059] and was significantly higher in the subjects with GG genotype compared to those with GT or TT genotype (9.5% vs. 6.6%, p = 0.0060). Multiple logistic regression analyses revealed that the number of G alleles (Odds ratio (OR) = 1.49 with 95% CI 1.09-2.05, p = 0.0125) and GG genotype (OR = 1.66 with 95% CI 1.13-2.43, p = 0.0098) were significantly associated with CVD even after adjustment for conventional risk factors. Interestingly, the presence of obesity further and significantly increased the risk of CVD in the subjects with GG genotype (OR = 1.67 with 95% CI 1.14-2.44, p = 0.0090) but not in the subjects with TT or GT genotype (OR = 1.17 with 95% CI 0.73-1.89, NS). Conclusions: It is likely that the G allele of the ADIPOQ G276T polymorphism is a susceptibility allele for CVD in Japanese type 2 diabetic patients, especially when they accompany obesity. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
  • Yukari Fujita; Daisuke Tamada; Junji Kozawa; Yoko Kobayashi; Shugo Sasaki; Tetsuhiro Kitamura; Tetsuyuki Yasuda; Norikazu Maeda; Michio Otsuki; Kohei Okita; Hiromi Iwahashi; Hideaki Kaneto; Tohru Funahashi; Akihisa Imagawa; Iichiro Shimomura
    INTERNAL MEDICINE 51 18 2581 - 2585 2012年 [査読有り]
     
    We herein describe a 59-year-old woman who had undergone a total gastrectomy for gastric carcinoma and suffered from postprandial hypoglycemia characterized by a loss of consciousness and spasms. She was diagnosed with reactive hypoglycemia and treated with nutrition therapy, but the frequency and severity of the hypoglycemic episodes did not decrease. She was subsequently treated successfully with miglitol, an alpha-glucosidase inhibitor (alpha-GI) taken twice a day; other alpha-GIs (acarbose and voglibose) were not effective. In conclusion, the administration of miglitol was effective for preventing reactive hypoglycemia secondary to late dumping syndrome.
  • Kana Inoue; Norikazu Maeda; Susumu Kashine; Yuya Fujishima; Junji Kozawa; Aki Hiuge-Shimizu; Kohei Okita; Akihisa Imagawa; Tohru Funahashi; Iichiro Shimomura
    CARDIOVASCULAR DIABETOLOGY 10 2011年12月 [査読有り]
     
    Background: To examine the effects of liraglutide, a glucagon-like peptide-1 (GLP-1) analogue, on visceral fat adiposity, appetite, food preference, and biomarkers of cardiovascular system in Japanese patients with type 2 diabetes. Methods: The study subjects were 20 inpatients with type 2 diabetes treated with liraglutide [age; 61.2 +/- 14.0 years, duration of diabetes; 16.9 +/- 6.6 years, glycated hemoglobin (HbA1c); 9.1 +/- 1.2%, body mass index (BMI); 28.3 +/- 5.2 kg/m(2), mean +/- SD]. After improvement in glycemic control by insulin or oral glucose-lowering agents, patients were switched to liraglutide. We assessed the estimated visceral fat area (eVFA) by abdominal bioelectrical impedance analysis, glycemic control by the 75-g oral glucose tolerance test (OGTT) and eating behavior by the Japan Society for the Study of Obesity questionnaire. Results: Treatment with liraglutide (dose range: 0.3 to 0.9 mg/day) for 20.0 +/- 6.4 days significantly reduced waist circumference, waist/hip ratio, eVFA. It also significantly improved the scores of eating behavior, food preference and the urge for fat intake and tended to reduce scores for sense of hunger. Liraglutide increased serum C-peptide immunoreactivity and disposition index. Conclusions: Short-term treatment with liraglutide improved visceral fat adiposity, appetite, food preference and the urge for fat intake in obese Japanese patients with type 2 diabetes.
  • Yukiko Imanishi; Shigeru Miyagawa; Norikazu Maeda; Satsuki Fukushima; Satoru Kitagawa-Sakakida; Takashi Daimon; Ayumu Hirata; Tatsuya Shimizu; Teruo Okano; Iichiro Shimomura; Yoshiki Sawa
    Circulation 124 11 Suppl S10-7  2011年09月 [査読有り]
     
    BACKGROUND: A drug delivery system that constitutively and effectively retains cardioprotective reagents in the targeted myocardium has long been sought to treat acute myocardial infarction. We hypothesized that a scaffold-free induced adipocyte cell-sheet (iACS), transplanted on the surface of the heart, might intramyocardially secrete multiple cardioprotective factors including adiponectin (APN), consequently attenuating functional deterioration after acute myocardial infarction. METHODS AND RESULTS: Induced ACS were generated from adipose tissue-derived cells of wild-type (WT) mice (C57BL/6J), which secreted abundant APN, hepatocyte growth factor, and vascular endothelial growth factor in vitro. Transplanted iACS secreted APN into the myocardium of APN-knockout (KO) mice at 4 weeks. APN was also detected in the plasma of iACS-transplanted APN-KO mice at 3 months (245 ± 113 pg/mL). After left anterior descending artery ligation, iACS, generated from either WT (n=40) or APN-KO (n=40) mice, were grafted onto the surface of the anterior left ventricular wall of WT mice, or only left anterior descending artery ligation was performed (n=43). Two days later, inflammation and infarct size were significantly diminished only in the WT-iACS treated mice. One month later, cardiomyocyte diameter and percent fibrosis were smaller, whereas ejection fraction and survival were greater in the WT-iACS treated mice compared with the KO-iACS-treated or nontreated mice. CONCLUSIONS: Cardioprotective factors including APN, hepatocyte growth factor, and vascular endothelial growth factor were secreted from iACS. Transplantation of iACS onto the acute myocardial infarction heart attenuated infarct size, inflammation, and left ventricular remodeling, mediated by intramyocardially secreted APN in a constitutive manner. This method might be a novel drug delivery system to treat heart disease.
  • Kaori Nakanishi; Yoshito Takeda; Satoshi Tetsumoto; Takeo Iwasaki; Kazuyuki Tsujino; Hanako Kuhara; Yingji Jin; Izumi Nagatomo; Hiroshi Kida; Sho Goya; Takashi Kijima; Norikazu Maeda; Tohru Funahashi; Iichiro Shimomura; Isao Tachibana; Ichiro Kawase
    AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE 183 9 1164 - 1175 2011年05月 [査読有り]
     
    Rationale: Chronic obstructive pulmonary disease is frequently complicated with comorbidities, such as cardiovascular disease, osteoporosis, and body weight loss, but the causal link remains unclear. Objectives: To investigate the role of adiponectin in the pathogenesis of chronic obstructive pulmonary disease and its potential use in therapy. Methods: Adiponectin localization and dynamics in the lung were analyzed in an elastase-induced emphysema model. Next, the lung of adiponectin-knockout mice, extrapulmonary effects, and the underlying mechanism were investigated. Finally, we tested whether exogenous adiponectin could ameliorate the emphysematous change in adiponectin-knockout mice. Measurements and Main Results: Adiponectin expression in lung vasculature and plasma concentration of adiponectin were reduced after elastase-instillation. Notably, adiponectin-knockout mice showed progressive alveolar enlargement and increased lung compliance. They further exhibited not only systemic inflammation, but also extrapulmonary phenotype, such as body weight loss, fat atrophy, and osteoporosis. Moreover, endothelial apoptosis was enhanced in the lungs of adiponectin-knockout mice, as evidenced by caspase-3 activity. Consistent with this, expressions of vascular endothelial growth factor receptor-2 and platelet endothelial cell adhesion molecule-1 on endothelial cells were decreased in the adiponectin-knockout mice. Finally, adenovirus-mediated adiponectin supplementation ameliorated the emphysematous phenotype. Conclusions: Adiponectin-knockout mice develop progressive chronic obstructive pulmonary disease-like phenotype with systemic inflammation and extrapulmonary phenotypes. Hypoadiponectinemia could thus play a critical role in the progression of chronic obstructive pulmonary disease and concomitant comorbidities through endothelial dysfunction. Together, adiponectin could be a novel target for chronic obstructive pulmonary disease therapy.
  • Maeda N; Shimomura I
    Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 100 4 911 - 916 2011年04月 [査読有り]
  • Aki Hiuge-Shimizu; Norikazu Maeda; Ayumu Hirata; Hideaki Nakatsuji; Kouichi Nakamura; Akira Okuno; Shinji Kihara; Tohru Funahashi; Iichiro Shimomura
    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 31 4 792 - 799 2011年04月 [査読有り]
     
    Objective-Accumulating evidence indicates that the regimen to increase adiponectin will provide a novel therapeutic strategy for metabolic syndrome. Here, we tested the effect of a potent and selective peroxisome proliferator-activated receptor-gamma agonist, rivoglitazone (Rivo), a newly synthesized thiazolidinedione derivative, on adiponectin, insulin resistance, and atherosclerosis. Methods and Results-ob/ob mice, apolipoprotein E knockout (apoE KO) mice, and apoE and adiponectin double knockout mice were administered pioglitazone, Rivo, or no compound. Remarkable elevation of plasma adiponectin was observed, especially in Rivo-treated ob/ob mice. Rivo ameliorated insulin resistance in ob/ob mice and reduced atherosclerotic areas in apoE KO mice compared with the pioglitazone group but failed to decrease atherosclerotic areas in double knockout mice. Among adipose mRNAs, adipose S100A8, which activates Toll-like receptor 4-dependent signal transduction cascades and locates upstream of inflammation, was markedly increased in ob/ob mice, and its increase was completely reversed by Rivo treatment. In RAW264.7 macrophage cells and 3T3-L1 adipocytes, Rivo significantly reduced S100A8 mRNA levels. Conclusion-The peroxisome proliferator-activated receptor-gamma agonist Rivo remarkably enhanced adiponectin in plasma and decreased adipose S100A8 mRNA levels in obese mice. Rivo treatment apparently ameliorated insulin resistance in ob/ob mice and reduced atherosclerosis in apoE KO mice, partly through adiponectin. (Arterioscler Thromb Vasc Biol. 2011;31:792-799.)
  • Maeda N; Hibuse T; Funahashi T; Shimomura I
    Nihon rinsho. Japanese journal of clinical medicine 69 Suppl 1 325 - 330 2011年01月 [査読有り]
  • Kana Inoue; Junji Kozawa; Tohru Funahashi; Yukiko Nakata; Eri Mitsui; Tetsuhiro Kitamura; Norikazu Maeda; Ken Kishida; Michio Otsuki; Kohei Okita; Hiromi Iwahashi; Akihisa Imagawa; Iichiro Shimomura
    INTERNAL MEDICINE 50 23 2893 - 2897 2011年 [査読有り]
     
    Acute suppurative thyroiditis is a rare disorder that is mostly found in the left lobe of the thyroid gland of children due to congenital patency of the pyriform sinus fistula. Here, we report a 61-year-old man with acute right-sided suppurative thyroiditis without pyriform sinus fistula. He also showed infectious hip arthritis, spondylitis and Roth's spots. He presented with heart failure and was diagnosed with infectious endocarditis by sequential transesophageal echocardiography. A replacement with a prosthetic valve was performed and cured him. It is important to recognize that infectious endocarditis can be a focus of acute suppurative thyroiditis.
  • Julie Jortay; Maximin Senou; Aurelie Delaigle; Laurence Noel; Tohru Funahashi; Norikazu Maeda; Marie C. Many; Sonia M. Brichard
    ENDOCRINOLOGY 151 10 4840 - 4851 2010年10月 [査読有り]
     
    Adiponectin (ApN) exhibits metabolic and antiinflammatory properties. This hormone is exclusively secreted by adipocytes under normal conditions. We have shown that ApN was induced in tibialis anterior muscle of mice injected with lipopolysaccharide (LPS) and in C2C12 myotubes cultured with proinflammatory cytokines. We hypothesized that muscle ApN could be a local protective mechanism to counteract excessive inflammatory reaction and oxidative damage. To test this paradigm, we examined whether muscles of ApN-knockout (KO) mice exhibit a higher degree of oxidative stress and apoptosis than wild-type mice when challenged by ip LPS and whether these abnormalities may be corrected by local administration of ApN. Eventually we investigated the effects of ApN in vitro. When compared with wild-type mice, ApN-KO mice exhibited myocyte degenerescence, especially after LPS. Myocytes of ApN-KO mice also displayed much stronger immunolabeling for markers of oxidative stress (peroxiredoxin-3/5 and heme oxygenase-1) as well as for a lipid peroxidation product (hydroxynonenal). Expression of TNF-alpha, caspase-6, a marker of apoptosis, and nuclear factor-kappa B was enhanced as well. Eventually muscle electrotransfer of the ApN gene, which did not induce any rise of systemic ApN, corrected all these abnormalities in LPS-injected ApN-KO mice. Likewise, ApN attenuated LPS-induced production of proinflammatory cytokines and activation of nuclear factor-kappa B in C2C12 cells. Thus, induction of ApN into skeletal muscle in response to an inflammatory aggression appears to be a crucial mechanism to counteract in an autocrine or paracrine fashion excessive inflammatory damage, oxidative stress, and subsequent apoptosis. (Endocrinology 151: 4840-4851, 2010)
  • Noriyuki Komura; Shinji Kihara; Mina Sonoda; Norikazu Maeda; Yoshihiro Tochino; Tohru Funahashi; Iichiro Shimomura
    CARDIOVASCULAR RESEARCH 86 3 471 - 477 2010年06月 [査読有り]
     
    Patients with chronic renal failure are at high risk of cardiovascular diseases. Previous studies in healthy population showed that hypoadiponectinemia was associated with high cardiovascular disease risk. However, plasma adiponectin (APN) levels are increased in renal dysfunction. Therefore, the clinical significance of plasma APN level in patients with moderate renal dysfunction is controversial. The aim of this study was to determine the change of plasma APN levels in a mouse model of renal failure and the loss of vasculo-protective function of APN in the presence of high cystatin C levels. Subtotal (5/6) nephrectomy was performed in APN-knockout (KO) mice and wild-type (WT) mice. The procedure in WT mice resulted in the significant increase of plasma APN and cystatin C levels. The clearance rate of APN was measured by injecting plasma from WT mice into KO mice. The clearance rate was significantly decreased in subtotal nephrectomized KO mice compared with sham-operated KO mice. Adiponectin protein and mRNA levels in adipose tissue were similar to subtotal nephrectomized and sham-operated mice. In cultured endothelial cells, at a high concentration corresponding to renal failure, cystatin C abolished the suppressive effects of APN on tumour necrosis factor alpha-induced expression of monocyte adhesion molecules. Plasma APN increases in chronic renal failure, at least in part due to low clearance rate. High concentrations of cystatin C abolish the vasculo-protective effect of APN.
  • Kuroda Y; Kuriyama H; Kihara S; Kishida K; Maeda N; Hibuse T; Nishizawa H; Matsuda M; Funahashi T; Shimomura I
    Horm Metab Res 42 3 173 - 177 2010年03月 [査読有り]
  • Koichi Fujita; Norikazu Maeda; Junji Kozawa; Kakeyoshi Murano; Kohei Okita; Hiromi Iwahashi; Shinji Kihara; Masato Ishigami; Motoko Omura; Tadashi Nakamura; Kohji Shirai; Taku Yamamura; Tohru Funahashi; Iichiro Shimomura
    INTERNAL MEDICINE 49 22 2467 - 2472 2010年 [査読有り]
     
    Lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) enhance the hydrolysis of triglycerides (TG) transported by chylomicron (CM) and very-low-density lipoprotein (VLDL). We report a case of severe hyperchylomicronemia with high levels of remnant lipoprotein and total cholesterol (T-Chol) in a 15-year-old boy. Precise examination of the lipid profile showed decreased activities of both LPL and HTGL, although the protein mass for LPL and HTGL were maintained. In addition, bezafibrate treatment effectively ameliorated hypertriglyceridemia in this case. This is the first case of hyperchylomicronemia with decreased activities and unaffected protein masses for both LPL and HTGL, without overt immuno-dysfunction.
  • Hideaki Nakatsuji; Norikazu Maeda; Toshiyuki Hibuse; Aki Hiuge; Ayumu Hirata; Yohei Kuroda; Ken Kishida; Shinji Kihara; Tohru Funahashi; Iichiro Shimomura
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 392 1 100 - 105 2010年01月 [査読有り]
     
    Atrial- and brain-type natriuretic peptides (ANP and BNP, respectively) have been shown to exert potent lipolytic action in adipocytes. A family of natriuretic peptide receptors (NPRs), NPR-1, NPR-2, and NPR-3, mediates their physiologic effects. NPR-1 and NPR-2 are receptor guanylyl cyclases, while NPR-3 lacks enzymatic activity and functions primarily as a clearance receptor for natriuretic peptides. ANP has a high affinity for NPR-1 and NPR-3 than other natriuretic peptides. There is a possibility that ANP may exhibit its lipolytic effect through the balance of NPR-1 and NPR-3 expressions in adipocytes. However, the regulation of adipose NPRs has not been fully elucidated. We here examined the regulation of mouse adipose NPRs by insulin, an anti-lipolytic hormone. Among the insulin target organs, NPR-1 mRNA levels were higher in white adipose tissue (WAT) than in liver and skeletal muscle. NPR-3 mRNA was expressed most abundantly in WAT. Fasting condition induced NPR-1 mRNA level while suppressed NPR-3 mRNA level in WAT. Administration of streptozotocin resulted in the increase of NPR-1 mRNA level while the decrease of NPR-3 mRNA level in WAT. In ob/ob mice, hyperinsulinemic model, NPR-1 m RNA level was lower whereas NPR-3 mRNA level was higher compared to lean control mice. In 3T3-L1 adipocytes, insulin significantly reduced NPR-1 mRNA level while increased NPR-3 mRNA levels both through phosphatidylinositol 3-kinase (PI3-kinase) pathway. In summary, NPR-1 and NPR-3 were highly expressed in WAT and adipose NPR-1 and NPR-3 were reciprocally regulated by insulin. This study suggests that insulin may efficiently promote lipogenesis partly by reducing the lipolytic action of ANP through the opposite regulation of NPR-1 and NPR-3. (C) 2010 Elsevier Inc. All rights reserved.
  • Baba Y; Yasuda O; Takemura Y; Ishikawa Y; Ohishi M; Iwanami J; Mogi M; Doe N; Horiuchi M; Maeda N; Fukuo K; Rakugi H
    Laboratory investigation; a journal of technical methods and pathology 89 12 1340 - 1347 2009年12月 [査読有り]
     
    Extracellular matrix (ECM) degradation is performed primarily by matrix metalloproteinases (MMPs). MMPs have recently been shown to regulate synaptic activity in the hippocampus and to affect memory and learning. The tissue inhibitor of metalloproteinase (Timp) is an endogenous factor that controls MMP activity by binding to the catalytic site of MMPs. At present, four Timp isotypes have been reported (Timp-1 through Timp-4) with 35-50% amino-acid sequence homology. Timp-3 is a unique member of Timp proteins in that it is bound to the ECM. In this study, we used the passive avoidance test, active avoidance test, and water maze test to examine the cognitive function in Timp-3 knockout (KO) mice. Habituation was evaluated using the open-field test. The water maze test showed that Timp-3 KO mice exhibit deterioration in cognitive function compared with wild-type (WT) mice. The open-field test showed decreased habituation of Timp-3 KO mice. Immunostaining of brain slices revealed the expression of Timp-3 in the hippocampus. In situ zymography of the hippocampus showed increased gelatinolytic activity in Timp-3 KO mice compared with WT mice. These results present the first evidence of Timp-3 involvement in cognitive function and hippocampal MMP activity in mice. Moreover, our findings suggest a novel therapeutic target to be explored for improvement of cognitive function in humans.
  • Ayumu Hirata; Norikazu Maeda; Aki Hiuge; Toshiyuki Hibuse; Koichi Fujita; Takuya Okada; Shinji Kihara; Tohru Funahashi; Iichiro Shimomura
    CARDIOVASCULAR RESEARCH 84 1 164 - 172 2009年10月 [査読有り]
     
    In obesity, chronic low-grade inflammation and overproduction of reactive oxygen species (ROS) in fat contribute to the development of metabolic syndrome. Suppression of inflammation and ROS production in fat may attenuate the metabolic syndrome. Activation of mineralocorticoid receptor (MR) promotes inflammation in heart, kidney, and vasculature via ROS generation. However, the significance of MR in fat remains elusive. Here we investigated whether MR blockade attenuates obesity-related insulin resistance and improves adipocyte dysfunction. Obese ob/ob and db/db mice were treated with eplerenone, a MR antagonist, for 3 weeks. 3T3-L1 adipocytes were treated with aldosterone or H(2)O(2), with and without eplerenone or MR-siRNA. High levels of MR mRNA were detected in adipose tissue of obese ob/ob and db/db mice. Eplerenone treatment significantly reduced insulin resistance, suppressed macrophage infiltration and ROS production in adipose tissues, and corrected the mRNA levels of obesity-related genes in obese mice. In 3T3-L1 adipocytes, aldosterone and H(2)O(2) increased intracellular ROS levels and MR blockade inhibited such increases. H(2)O(2) and aldosterone resulted in dysregulation of mRNAs of various genes related to ROS and cytokines, whereas MR blockade corrected such changes. MR blockade attenuates obesity-related insulin resistance partly through reduction of fat ROS production, inflammatory process, and induction of cytokines.
  • Hibuse T; Maeda N; Nakatsuji H; Tochino Y; Fujita K; Kihara S; Funahashi T; Shimomura I
    Cardiovascular research 83 1 34 - 41 2009年07月 [査読有り]
  • Osamu Tsukamoto; Masashi Fujita; Mahoto Kato; Satoru Yamazaki; Yoshihiro Asano; Akiko Ogai; Hidetoshi Okazaki; Mitsutoshi Asai; Yoko Nagamachi; Norikazu Maeda; Yasunori Shintani; Tetsuo Minamino; Masanori Asakura; Ichiro Kishimoto; Tohru Funahashi; Hitonobu Tomoike; Masafumi Kitakaze
    JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 53 22 2070 - 2077 2009年06月 [査読有り]
     
    Objectives We investigated the functional relationship between natriuretic peptides and adiponectin by performing both experimental and clinical studies. Background Natriuretic peptides are promising candidates for the treatment of congestive heart failure (CHF) because of their wide range of beneficial effects on the cardiovascular system. Adiponectin is a cytokine derived from adipose tissue with various cardiovascular-protective effects that has been reported to show a positive association with plasma brain natriuretic peptide (BNP) levels in patients with heart failure. Methods The expression of adiponectin messenger ribonucleic acid (mRNA) and its secretion were examined after atrial natriuretic peptide (ANP) or BNP was added to primary cultures of human adipocytes in the presence or absence of HS142-1 (a functional type A guanylyl cyclase receptor antagonist). Changes of the plasma adiponectin level were determined in 30 patients with CHF who were randomized to receive intravenous ANP (0.025 mu g/kg/min human ANP for 3 days, n = 15) or saline (n = 15). Results Both ANP and BNP dose-dependently enhanced the expression of adiponectin mRNA and its secretion, whereas such enhancement was inhibited by pre-treatment with HS142-1. The plasma adiponectin level was increased at 4 days after administration of human ANP compared with the baseline value (from 6.56 +/- 0.40 mu g/ml to 7.34 +/- 0.47 mu g/ml, p < 0.05), whereas there was no change of adiponectin in the saline group (from 6.53 +/- 0.57 mu g/ml to 6.55 +/- 0.56 mu g/ ml). Conclusions Natriuretic peptides enhance adiponectin production by human adipocytes in vitro and even in patients with CHF, which might have a beneficial effect on cardiomyocytes in patients receiving recombinant natriuretic peptide therapy for heart failure. (J Am Coll Cardiol 2009;53:2070-7) (C) 2009 by the American College of Cardiology Foundation
  • Megumi Kondo; Rei Shibata; Rie Miura; Masayuki Shimano; Kazuhisa Kondo; Ping Li; Taiki Ohashi; Shinji Kihara; Norikazu Maeda; Kenneth Walsh; Noriyuki Ouchi; Toyoaki Murohara
    JOURNAL OF BIOLOGICAL CHEMISTRY 284 3 1718 - 1724 2009年01月 [査読有り]
     
    Caloric restriction (CR) can extend longevity and modulate the features of obesity-related metabolic and vascular diseases. However, the functional roles of CR in regulation of revascularization in response to ischemia have not been examined. Here we investigated whether CR modulates vascular response by employing a murine hindlimb ischemia model. Wild-type (WT) mice were randomly divided into two groups that were fed either ad libitum (AL) or CR (65% of the diet consumption of AL). Four weeks later, mice were subjected to unilateral hindlimb ischemic surgery. Body weight of WT mice fed CR (CR-WT) was decreased by 26% compared with WT mice fed AL (AL-WT). Revascularization of ischemic hindlimb relative to the contralateral limb was accelerated in CR-WT compared with AL-WT as evaluated by laser Doppler blood flow and capillary density analyses. CR-WT mice had significantly higher plasma levels of the fat-derived hormone adiponectin compared with AL-WT mice. In contrast to WT mice, CR did not affect the revascularization of ischemic limbs of adiponectindeficient (APN-KO) mice. CR stimulated the phosphorylation of endothelial nitric-oxide synthase (eNOS) in the ischemic limbs of WT mice. CR increased plasma adiponectin levels in eNOS-KO mice but did not stimulate limb perfusion in this strain. CR-WT mice showed enhanced phosphorylation of AMP-activated protein kinase (AMPK) in ischemic muscle, and administration of AMPK inhibitor compound C abolished CR-induced increase in limb perfusion and eNOS phosphorylation in WT mice. Our observations indicate that CR can promote revascularization in response to tissue ischemia via an AMPK-eNOS-dependent mechanism that is mediated by adiponectin.
  • Norikazu Maeda; Toshiyuki Hibuse; Tohru Funahashi
    Handbook of Experimental Pharmacology 190 233 - 249 2009年 [査読有り]
     
    The discovery of aquaporin (AQP) has had a great impact on life sciences. So far, 13 AQPs have been identified in human. AQP3, 7, 9, and 10 are subcategorized as aquaglyceroporins which permeabilize glycerol as well as water. Many investigators have demonstrated that AQPs play a crucial role in maintaining water homeostasis, but the physiological significance of some AQPs as a glycerol channel has not been fully understood. Adipocyte is considered to be a major source of glycerol which is one of substrates for hepatic gluconeogenesis. This review focuses on recent studies of glycerol metabolism through AQP7 and AQP9, and discusses the importance of glycerol channel in adipose tissues and liver. © 2009 Springer Berlin Heidelberg.
  • Norikazu Maeda; Tohru Funahashi; Fichiro Shimomura
    NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM 4 11 627 - 634 2008年11月 [査読有り]
     
    The discovery of aquaporins, which are plasma-membrane-associated water channels, has greatly influenced the medical sciences. So far, thirteen aquaporins have been identified in humans. Among them, types 3, 7,9, an 10 are subcategorized as aquaglyceroporins, which enable the transport of glycerol as well as water. Although aquaporins have a proven crucial to e in water homeostasis, the physiological and pathological importance of aquaporins as glycerol channels is not fully understood. Adipocytes are a major source of glycerol, one of the substrates for hepatic gluconeogenesis. Aquaporin subtypes 7 and 9 (AQP7 and AQP9) are the glycerol channels in adipocytes and hepatocytes, respectively. The coordinated regulation of these channels leads to the optimum balance between release of glycerol by adipocytes and its uptake by the liver. In addition, studies of AQP7 and AQP9 knockout or knockdown mice have clearly demonstrated in vivo the pathophysiological relevance of glycerol channels through effects on glycerol metabolism. Associations between various AQP7 gene mutations and obesity in humans have also been shown. Thus, further research of these two aquaporins might uncover novel targets for therapy.
  • Kazumi Tsubakio-Yamamoto; Fumihiko Matsuura; Masahiro Koseki; Hiroyuki Oku; Jose C. Sandoval; Miwako Inagaki; Kazuhiro Nakatani; Hajime Nakaoka; Ryota Kawase; Miyako Yuasa-Kawase; Daisaku Masuda; Tohru Ohama; Norikazu Maeda; Yumiko Nakagawa-Toyama; Masato Ishigami; Makoto Nishida; Shinji Kihara; Iichiro Shimomura; Shizuya Yamashita
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 375 3 390 - 394 2008年10月 [査読有り]
     
    Plasma high density lipoprotein (HDL)-cholesterol levels are inversely correlated to the risk of atherosclerotic cardiovascular diseases. Reverse cholesterol transport (RCT) is one of the major protective systems against atherosclerosis, in which HDL particles play a crucial role to carry cholesterol derived from peripheral tissues to the liver. Recently, ATP-binding cassette transporters (ABCA1, ABCG1) and scavenger receptor (SR-BI) have been identified as important membrane receptors to generate HDL by removing cholesterol from foam cells. Adiponectin (APN) secreted from adipocytes is one of the important molecules to inhibit the development of atherosclerosis. Epidemiological Studies have revealed a positive correlation between plasma HDL-cholesterol and APN concentrations in humans, although its mechanism has not been clarified. Therefore, in the present study, we investigated the role of APN on RCT, in particular, cellular cholesterol efflux from human monocyte-derived and APN-knockout (APN-KO) mice macrophages. APN up-regulated the expression of ABCA1 in human macrophages, respectively. ApoA-1-mediated cholesterol efflux from macrophages was also increased by APN treatment. Furthermore, the mRNA expression of LXR alpha. and PPAR gamma was increased by APN. In APN-KO mice, the expression of ABCA1, LXRa, PPAR 1, and apoA-I-mediated cholesterol efflux was decreased compared with wild-type mice. In summary, APN might protect against atherosclerosis by increasing apoA-I-mediated cholesterol efflux from macrophages through ABCA1-dependent pathway by the activation of LXR alpha and PPAR gamma. (C) 2008 Published by Elsevier Inc.
  • Koichi Fujita; Norikazu Maeda; Mina Sonoda; Koji Ohashi; Toshiyuki Hibuse; Hitoshi Nishizawa; Makoto Nishida; Aki Hiuge; Akifumi Kurata; Shinji Kihara; Iichiro Shimomura; Tohru Funahashi
    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 28 5 863 - 870 2008年05月 [査読有り]
     
    Objectives-Adiponectin is recognized as an antidiabetic, antiatherosclerotic, and anti-inflammatory protein derived from adipocytes. However, the role of adiponectin in cardiac fibrosis remains uncertain. We herein explore the effects of adiponectin on cardiac fibrosis induced by angiotensin II (Ang II). Methods and Results-Wild-type (WT), adiponectin knockout (Adipo-KO), and PPAR-alpha knockout (PPAR-alpha-KO) mice were infused with Ang II at 1.2 mg/kg/d. Severe cardiac fibrosis and left ventricular dysfunction were observed in Ang II-infused Adipo-KO mice compared to WT mice. Adenovirus-mediated adiponectin treatment improved the above phenotypes and the dysregulation of reactive oxygen species (ROS)-related mRNAs in Adipo-KO mice, whereas such amelioration was not observed in PPAR-alpha-KO mice despite adiponectin accumulation in heart tissue. In cultured cardiac fibroblasts, adiponectin improved the reduction of AMP-activated protein kinase (AMPK) activity and elevation of extracellular signal-regulated kinase 1/2 (ERK1/2) activity induced by Ang II. Adiponectin significantly enhanced PPAR-alpha activity, whereas the adiponectin-dependent PPAR-alpha activation was diminished by Compound C, an inhibitor of AMPK. Conclusion-The present study suggests that adiponectin protects against Ang II-induced cardiac fibrosis possibly through AMPK-dependent PPAR-alpha activation.
  • Takuya Okada; Hitoshi Nishizawa; Akifunii Kurata; Sachiko Tamba; Mina Sonoda; Atsutaka Yasui; Yohei Kuroda; Toshiyuki Hibuse; Norikazu Maeda; Shinji Kihara; Tohru Hadama; Kazuki Tobita; Suguru Akamatsu; Kazuhisa Maeda; Iichiro Shimomura; Tohru Funahashi
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 367 2 370 - 376 2008年03月 [査読有り]
     
    Dysregulated production of adipocytokines in obesity is involved in the development of metabolic syndrome. URB/DRO1 contains N-terminal signal sequence and is thought to play a role in apoptosis of tumor cells. In the present study, we investigated the expression pattern of URB mRNA in adipose tissue and secretion from cultured adipocytes. In human and mouse, URB mRNA was predominantly expressed in adipose tissue and was downregulated in obese mouse models, such as ob/ob, KKAy, and diet-induced obese mice. In 3T3L1 adipocytes, insulin, TNF-alpha, H2O2 and hypoxia decreased URB mRNA level. This regulation was similar to that for adiponectin and opposite to MCP-1. URB protein was secreted in media of URB cDNA-stably transfected cells and endogenous URB was detected in media of cultured human adipocytes. In conclusion, the expression pattern of URB suggests its role in obesity and the results suggest that URB is secreted, at least in part, from adipocytes. (c) 2007 Elsevier Inc. All rights reserved.
  • Hiroyuki Oku; Fumihiko Matsuura; Masahiro Koseki; Jose C. Sandoval; Miyako Yuasa-Kawase; Kazumi Tsubakio-Yamamoto; Daisaku Masuda; Norikazu Maeda; Tohru Ohama; Masato Ishigami; Makoto Nishida; Ken-Ichi Hirano; Shinji Kihara; Masatsugu Hori; Iichiro Shimomura; Shizuya Yamashita
    FEBS LETTERS 581 26 5029 - 5033 2007年10月 [査読有り]
     
    Plasma high density lipoprotein (HDL)-cholesterol levels are inversely correlated with the incidence of cardiovascular diseases. HDL is mainly assembled in the liver through the ATP-binding cassette transporter (ABCA1) pathway. In humans, plasma HDL-cholesterol levels are positively correlated with plasma adiponectin (APN) concentrations. Recently, we reported that APN enhanced apolipoprotein A-I (apoA-I) secretion and ABCA1 expression in HepG2 cells. In the present study, we investigated HDL assembly in APN-knockout (KO) mice. The apoA-I protein levels in plasma and liver were reduced in APN-KO mice compared with wild-type-mice. The ABCA1 expression in liver was also decreased in APN-KO mice. APN deficiency might cause the impaired HDL assembly by decreasing ABCA1 expression and apoA-I synthesis in the liver. (C) 2007 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
  • Yoshihiro Kamada; Hitoshi Matsumoto; Shinji Tamura; Juichi Fukushima; Shinichi Kiso; Koji Fukui; Takumi Igura; Norikazu Maeda; Shinji Kihara; Tohru Funahashi; Yuji Matsuzawa; Lichiro Shimomura; Norio Hayashi
    JOURNAL OF HEPATOLOGY 47 4 556 - 564 2007年10月 [査読有り]
     
    Background/Aims: Adipose tissue produces a number of adipocytokines, including adiponectin, leptin, and tumor necrosis factor-alpha. Obesity, which is associated with low plasma adiponectin levels, is an independent risk factor for various liver diseases including nonalcoholic steatohepatitis (NASH). The aim of this study was to examine the effects of adiponectin on the progression of NASH to cirrhosis and tumor formation using adiponectin-knockout (KO) mice. Methods: Using a choline-deficient L-amino acid-defined (CDAA) diet-induced mouse NASH model, liver histology and oxidative stress markers were investigated in KO and wild-type (WT) mice. Results: Hepatic steatosis was enhanced to a greater extent in KO mice, compared to WT mice after a 1-week CDAA diet. After 24 weeks, 6 out of 14 KO mice developed liver cirrhosis and hepatic tumors, whereas the 15 WT mice showed only simple steatosis. In KO mice, hepatic cytochrome P450 2E1 levels were upregulated, and markers of oxidative stress (thiobarbituric acid reactive substances, 8-hydroxydeoxyguanosine-positive cells) were significantly increased compared with WT mice. Conclusions: Our results indicate that lack of adiponectin enhances the progression of hepatic steatosis, fibrosis, and hepatic tumor formation in an animal model of NASH. Hypoadiponectinemia in obesity could be a risk factor for NASH-related hepatic tumor formation. (C) 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
  • Koji Ohashi; Hirotsugu Iwatani; Shinji Kihara; Yasuhiko Nakagawa; Noriyuki Komura; Koichi Fujita; Norikazu Maeda; Makoto Nishida; Fumie Katsube; Iichiro Shimomura; Takahito Ito; Tohru Funahashi
    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 27 9 1910 - 1917 2007年09月 [査読有り]
     
    Objective - Obesity is recognized increasingly as a major risk factor for kidney disease. We reported previously that plasma adiponectin levels were decreased in obesity, and that adiponectin had defensive properties against type 2 diabetes and hypertension. In this study, we investigated the role of adiponectin for kidney disease in a subtotal nephrectomized mouse model. Methods and Results - Subtotal (5/6) nephrectomy was performed in adiponectin-knockout (APN-KO) and wild-type (WT) mice. The procedure resulted in significant accumulation of adiponectin in glomeruli and interstitium in the remnant kidney. Urinary albumin excretion, glomerular hypertrophy, and tubulointerstitial fibrosis were significantly worse in APN-KO mice compared with WT mice. Intraglomerular macrophage infiltration and mRNA levels of vascular cell adhesion molecule (VCAM)-1, MCP-1, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta 1, collagen type I/III, and NADPH oxidase components were significantly increased in KO mice compared with WT mice. Treatment of APN-KO mice with adenovirus-mediated adiponectin resulted in amelioration of albuminuria, glomerular hypertrophy, and tubulointerstitial fibrosis and reduced the elevated levels of VCAM-1, MCP-1, TNF-alpha, TGF-beta 1, collagen type I/III, and NADPH oxidase components mRNAs to the same levels as those in WT mice. Conclusions - Adiponectin accumulates to the injured kidney, and prevents glomerular and tubulointerstitial injury through modulating inflammation and oxidative stress.
  • Fumihiko Matsuura; Hiroyuki Oku; Masahiro Koseki; Jose C. Sandoval; Miyako Yuasa-Kawase; Kazumi Tsubakio-Yamamoto; Daisaku Masuda; Norikazu Maeda; Ken-ichi Tsujii; Masato Ishigami; Makoto Nishida; Ken-ichi Hirano; Shinji Kihara; Masatsugu Hori; Iichiro Shimomura; Shizuya Yamashita
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 358 4 1091 - 1095 2007年07月 [査読有り]
     
    Plasma high density lipoprotein (HDL)-cholesterol levels are negatively correlated with the incidence of coronary artery disease. HDL plays an important role in protecting against atherosclerosis by removing cholesterol from atheroma and transporting it back to the liver. The ATP-binding cassette transporters (ABCA1 and ABCG1) and scavenger receptor BI (SR-BI) are thought to be one of the rate-limiting factors to generate HDL in the liver. Adiponectin (APN) secreted from adipocytes is also one of the important molecules to inhibit the development of atherosclerosis. Recently, it has been reported that plasma HDL-cholesterol levels are positively correlated with plasma APN concentrations in humans. Therefore, we investigated the association of APN with HDL assembly in the liver. Human hepatoma cell line, HepG2 cells, were incubated for 24 h in the culture medium with the indicated concentrations of recombinant APN. APN enhanced the mRNA level of apolipoprotein A-I (apoA-I) in HepG2 cells and increased the secretion of apoA-I from the cells to the medium. Furthermore, APN increased both mRNA and protein levels of ABCA 1, but not ABCG1 and SR-BI, in HepG2 cells. Taken together, the current study demonstrates that APN might protect against atherosclerosis by increasing HDL assembly through enhancing ABCA1 pathway and apoA-I synthesis in the liver. (C) 2007 Elsevier Inc. All rights reserved.
  • Higuchi M; Yasuda O; Kawamoto H; Yotsui T; Baba Y; Ozaki T; Maeda N; Fukuo K; Rakugi H; Ogihara T
    Hypertension research : official journal of the Japanese Society of Hypertension 30 6 563 - 571 2007年06月 [査読有り]
  • Isabelle B. Bauche; Samira Ait El Mkadem; Anne-Marie Pottier; Maximin Senou; Marie-Christine Many; Rene Rezsohazy; Luc Penicaud; Norikazu Maeda; Tohru Funahashi; Sonia M. Brichard
    ENDOCRINOLOGY 148 4 1539 - 1549 2007年04月 [査読有り]
     
    Adiponectin (ApN) is an adipokine whose expression and plasma levels are inversely related to obesity and insulin-resistant states. Chronic repercussions of ApN treatment or overexpression on adiposity and body weight are still controversial. Here, we generated a transgenic (Tg) mouse model allowing persistent and moderate overexpression of native full-length ApN targeted to white adipose tissue. Adipose mass and adipocyte size of Tg mice were reduced despite preserved calorie intake. This reduction resulted from increased energy expenditure and up-regulation of uncoupling proteins, and from abrogation of the adipocyte differentiation program, as shown by the loss of a key lipogenic enzyme and of adipocyte markers. Adipose mass remodeling favors enhanced insulin sensitivity and improved lipid profile of Tg mice. Alteration of the adipocyte phenotype was likely to result from increased expression of the preadipocyte factor-1 and from down-regulation of the transcription factor, CCAAT/enhancer binding protein-alpha, which orchestrates adipocyte differentiation. We further found that recombinant ApN directly stimulated preadipocyte factor-1 mRNA and attenuated CCAAT/enhancer binding protein-alpha expression in cultured 3T3-F442A cells. Conversely, opposite changes in the expression of these genes were observed in white fat of ApN-deficient mice. Thus, besides enhanced energy expenditure, our work shows that impairment of adipocyte differentiation contributes to the anti-adiposity effect of ApN.
  • Aki Hiuge; Alexander Tenenbaum; Norikazu Maeda; Michal Benderly; Masahiro Kumada; Enrique Z. Fisman; David Tanne; Zipora Matas; Toshiyuki Hibuse; Koichi Fujita; Hitoshi Nishizawa; Yehuda Adler; Michael Motro; Shinji Kihara; Iichiro Shimomura; Solomon Behar; Tohru Funahashi
    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 27 3 635 - 641 2007年03月 [査読有り]
     
    Objective - Adiponectin is adipose-specific secretory protein and acts as anti-diabetic and anti-atherosclerotic molecule. We previously found peroxisome proliferators response element in adiponectin promoter region, suggesting that peroxisome proliferator-activated receptor (PPAR) ligands elevate adiponectin. Fibrates are known to be PPAR alpha ligands and were shown to reduce risks of diabetes and cardiovascular disease. Effect of fibrates on adiponectin has not been clarified, whereas thiazolidinediones enhance adiponectin. Thus, we explored the possibility and mechanism that fibrates enhance adiponectin in humans, mice, and cells. Methods and Results - Significant increase of serum adiponectin was observed in bezafibrate-treated subjects compared with placebo group in patients enrolled in The Bezafibrate Infarction Prevention study. Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes. Fibrates, bezafibrate and fenofibrate, significantly elevated adiponectin levels in wild-type mice and 3T3-L1 adipocytes. Such an effect was not observed in PPAR alpha-deficient mice and adipocytes. Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPAR alpha was knocked down by PPAR alpha-RNAi. Conclusions - Our results suggest that fibrates enhance adiponectin partly through adipose PPAR alpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes.
  • A. Kurata; H. Nishizawa; S. Kihara; N. Maeda; M. Sonoda; T. Okada; K. Ohashi; T. Hibuse; K. Fujita; A. Yasui; A. Hiuge; M. Kumada; H. Kuriyama; I. Shimomura; T. Funahashi
    Kidney International 70 10 1717 - 1724 2006年11月
  • Yasuda O; Fukuo K; Sun X; Nishitani M; Yotsui T; Higuchi M; Suzuki T; Rakugi H; Smithies O; Maeda N; Ogihara T
    The Journal of biological chemistry 281 33 23899 - 23907 2006年08月 [査読有り]
  • Toshiyuki Hibuse; Norikazu Maeda; Azumi Nagasawa; Tohru Funahashi
    BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 1758 8 1004 - 1011 2006年08月 [査読有り]
     
    The discovery of aquaporin (AQP) has made a great impact on life sciences. AQPs are a family of homologous water channels widely distributed in plants, unicellular organisms, invertebrates, and vertebrates. So far, 13 AQPs have been identified in human. AQP3, 7, 9, and 10 are subcategorized as aquaglyceroporins which permeabilize glycerol as well as water. Many investigators have demonstrated that AQPs play a crucial role in maintaining water homeostasis, but the physiological significance of some AQPs as a glycerol channel is not fully understood. Adipose tissue is a major source of glycerol and glycerol is one of substrates for gluconeogenesis. This review focuses on recent studies of glycerol metabolism through aquaglyceroporins, and briefly discusses the importance of glycerol channel in adipose tissues and liver. (c) 2006 Elsevier B.V. All rights reserved.
  • IB Bauche; SA El Mkadem; R Rezsohazy; T Funahashi; N Maeda; LM Miranda; SM Brichard
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 345 4 1414 - 1424 2006年07月 [査読有り]
     
    Adiponectin (ApN) is an adipokine whose expression and plasma levels are inversely related to obesity and insulin-resistant states. The in vivo effects of a chronic expression of exogenous ApN restricted to adipose tissue are unclear. Moreover, the regulatory effects of ApN on its own expression and on that of its receptors are still unknown. In this study, we generated transgenic (Tg) mice with moderate expression of exogenous ApN targeted to adipose tissue (native full-length ApN being placed under control of the adipocyte promoter aP2). After a transient overexpression of ApN in young pups, we intriguingly observed a reduction of ApN mRNA levels and protein content in fat depots, together with a decrease of circulating ApN in adult mice. As a result, the phenotype of these adult mice included glucose intolerance, insulin resistance, and increased adiposity. Reduced expression of ApN in fat tissue was associated with diminished expression of uncoupling protein 2 involved in energy dissipation, and higher expression of fatty acid synthase, a key enzyme of lipogenesis, and of TNF alpha implicated in insulin resistance. Concomitantly, the expression of the ApN receptor AdipoR2 that mediates action of full-length ApN was downregulated, while that of AdipoR1 was unaffected. In agreement with the in vivo studies, recombinant ApN added to the culture medium of 3T3-F442A adipocytes caused a decrease in AdipoR2 and ApN mRNA levels. This treatment did not affect the expression of AdipoR1. Eventually, we demonstrated a contrario that AdipoR2 (but not R1) was specifically upregulated in fat of ApN(-/-) mice. Our in vivo and in vitro data provide evidence for a novel regulatory feedback loop by which ApN downregulates its own production and the expression of its AdipoR2 receptor. (c) 2006 Elsevier Inc. All rights reserved.
  • K Ohashi; S Kihara; N Ouchi; M Kumada; K Fujita; A Hiuge; T Hibuse; M Ryo; H Nishizawa; N Maeda; K Maeda; R Shibata; K Walsh; T Funahashi; Shimomura, I
    HYPERTENSION 47 6 1108 - 1116 2006年06月 [査読有り]
     
    Patients with obesity are susceptible to hypertension. We have reported that the plasma adiponectin levels are decreased in obesity and that adiponectin has many defensive properties against obesity-related diseases, such as type 2 diabetes and coronary artery disease. The aim of this study was to determine the relationship between adiponectin and hypertension in mice. We measured blood pressure and heart rate directly by a catheter in the carotid artery and indirectly by automatic sphygmomanometer at the tail artery. Obese KKAy mice had significantly lower plasma adiponectin levels and higher systolic blood pressure than control C57BL/6J mice at 21 weeks of age. Adenovirus-elivered adiponectin significantly decreased blood pressure in KKAy mice. The direct role of adiponectin on blood pressure regulation under insulin resistance-free state was investigated in adiponectin-knockout (KO) mice. Adiponectin KO mice developed hypertension when maintained on a high-salt diet (8% NaCl) without insulin resistance. The hypertension of salt-fed adiponectin KO mice was associated with reduced mRNA levels of endothelial NO synthase (eNOS) and prostaglandin I-2 synthase in aorta and low metabolite levels of endothelial NO synthase and prostaglandin I2 synthase in plasma. Adiponectin therapy lowered the elevated blood pressure and corrected the above mRNA levels to those of the wild type. Our results suggest that hypoadiponectinemia contributes to the development of obesity-related hypertension, at least in part, directly, in addition to its effect via insulin resistance, and that adiponectin therapy can be potentially useful for hypertension in patients with the metabolic syndrome.
  • Hitoshi Matsumoto; Shinji Tamura; Yoshihiro Kamada; Shinichi Kiso; Juichi Fukushima; Akira Wada; Norikazu Maeda; Shinji Kihara; Tohru Funahashi; Yuji Matsuzawa; Iichiro Shimomura; Norio Hayashi
    WORLD JOURNAL OF GASTROENTEROLOGY 12 21 3352 - 3358 2006年06月 [査読有り]
     
    AIM: To examine the effects of adiponectin on the functions of Kupffer cells, key modulators of lipopolysaccharide (LPS)-induced liver injury. METHODS: D-galactosamine (GalN) and LPS were injected intraperitoneally into adiponectin-/- mice and wild type mice. Kupffer cells, isolated from Sprague-Dawley rats, were preincubated with or without adiponectin, and then treated with LPS. RESULTS: In knockout mice, GalN/LPS injection significantly lowered the survival rate, significantly raised the plasma levels of alanine transaminase and tumor necrosis factor-alpha (TNF-alpha) and significantly reduced IL-10 levels compared with wild type mice. TNF-alpha gene expression in the liver was which higher and those of IL-10 were lower in knockout mice than in wild type mice. In cultured adiponectin-pre-treated Kupffer cells, LPS significantly lowered TNF-alpha levels and raised IL-10,levels in the culture media and their respective gene expression levels, compared with Kupffer cells without adiponectin-pre-treatment. CONCLUSION: Adiponectin supresses TNF-alpha production and induces IL-10 production by Kupffer cells in response to LPS stimulation, and a lack of adiponectin enhances I LPS-induced liver injury. (C) 2006 The WJG Press. All rights reserved.
  • Kawamoto H; Yasuda O; Suzuki T; Ozaki T; Yotsui T; Higuchi M; Rakugi H; Fukuo K; Ogihara T; Maeda N
    Hypertension research : official journal of the Japanese Society of Hypertension 29 4 285 - 294 2006年04月 [査読有り]
  • T. Funahashi; A. Nagasawa; T. Hibuse; N. Maeda
    CELLULAR AND MOLECULAR BIOLOGY 52 7 40 - 45 2006年 [査読有り]
     
    Glycerol is one of the essential nutrients in the mammalian body. Glycerol released from adipocytes is delivered to the liver and used for gluconeogenesis. The molecular mechanism of glycerol transport across the cell membrane remains unclear. AQPadipose, which we identified in human adipose cDNA project and later found to be human AQP7, is expressed in adipose tissue, and upregulated during fasting. AQP7 belongs to the aquaglyceroporin subfamily to permealize glycerol as well as water. Loss of function mutation of AQP7 in human caused disturbance of normal rise of plasma glycerol. Disruption of AQP7 gene in mice resulted in profound hypoglycemia during prolonged fasting because of impaired glycerol supply to the liver. In obesity, AQP7 is overexpressed in visceral fat, accompanied by portal hyperglycerolemia and systemic hyperglycemia. Considered together, these works indicate that AQP7 functions as a glycerol gateway molecule in adipocytes.
  • H Kato; H Kashiwagi; M Shiraga; S Tadokoro; T Kamae; H Ujiie; S Honda; S Miyata; Y Ijiri; J Yamamoto; N Maeda; T Funahashi; Y Kurata; Shimomura, I; Y Tomiyama; Y Kanakura
    ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 26 1 224 - 230 2006年01月 [査読有り]
     
    Objective: Obesity is a common risk factor in insulin resistance and cardiovascular diseases. Although hypoadiponectinemia is associated with obesity-related metabolic and vascular diseases, the role of adiponectin in thrombosis remains elusive. Methods and Results: We investigated platelet thrombus formation in adiponectin knockout (APN-KO) male mice (8 to 12 weeks old) fed on a normal diet. There was no significant difference in platelet counts or coagulation parameters between wild-type (WT) and APN-KO mice. However, APN-KO mice showed an accelerated thrombus formation on carotid arterial injury with a He-Ne laser (total thrombus volume: 13.36 +/- 4.25 x 10(7) arbitrary units for APN-KO and 6.74 +/- 2.87 x 10(7) arbitrary units for WT; n = 10; P < 0.01). Adenovirus-mediated supplementation of adiponectin attenuated the enhanced thrombus formation. In vitro thrombus formation on a type I collagen at a shear rate of 250 s(-1), as well as platelet aggregation induced by low concentrations of agonists, was enhanced in APN-KO mice, and recombinant adiponectin inhibited the enhanced platelet aggregation. In WT mice, adenovirus-mediated overexpression of adiponectin additionally attenuated thrombus formation. Conclusion: Adiponectin deficiency leads to enhanced thrombus formation and platelet aggregation. The present study reveals a new role of adiponectin as an endogenous antithrombotic factor.
  • Liao Y; Takashima S; Maeda N; Ouchi N; Komamura K; Shimomura I; Hori M; Matsuzawa Y; Funahashi T; Kitakaze M
    Cardiovasc Res. 67 4 705 - 713 2005年09月 [査読有り]
     
    Objective: Insulin resistance (IR) was reported to be associated with chronic heart failure (CHF). Adiponectin, an insulin-sensitizing hormone with anti-inflammatory activity, improves energy metabolism via AMP-activated protein kinase (AMPK). AMPK deficiency is associated with depressed cardiac function under stress conditions. However, it is not clear whether adiponectin plays an important role in CHF. We hypothesize that deficiency of adiponectin might result in deterioration of heart failure. Methods: Using adiponectin null mice and their littermates, we examined the effects of adiponectin on LV pressure overload-induced cardiac hypertrophy and failure, and investigated the mechanisms involved. Results: Three weeks after transverse aortic constriction (TAC), cardiac hypertrophy (evaluated from the heart-to-body weight ratio: 7.62 ± 0.27 in wild-type (WT) mice, 9.97 ± 1.13 in knockout (KO) mice, P < 0.05) and pulmonary congestion (lung-to-body weight ratio: 9.05 ± 1.49 in WT mice, 14.95 ± 2.36 in KO mice, P < 0.05) were significantly greater in adiponectin KO mice than WT mice. LV dimensions were also increased in KO mice. Compared with WT TAC mice, expression of AMPKα protein was lower, while IR was higher in KO TAC mice. Conclusion: These findings indicate that adiponectin deficiency leads to progressive cardiac remodeling in pressure overloaded condition mediated via lowing AMPK signaling and impaired glucose metabolism. © 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
  • T Hibuse; N Maeda; T Funahashi; K Yamamoto; A Nagasawa; W Mizunoya; K Kishida; K Inoue; H Kuriyama; T Nakamura; T Fushiki; S Kihara; L Shimomura
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 102 31 10993 - 10998 2005年08月 [査読有り]
     
    In adipocytes, hydrolysis of triglycerides results in the release of free fatty acids and glycerol. Aquaporin 7 (AQP7), a member of aquaglyceroporins, is known to permeabilize glycerol and water. We recently generated Aqp7-knockout (KO) mice and demonstrated that such mice have low plasma glycerol levels and impaired glycerol release in response to beta 3-adrenergic agonist, suggesting that AQP7 acts as a glycerol gateway molecule in adipocytes for the efficient release of glycerol in vivo. Although there was no difference in body weight between WT and KO mice until 10 weeks of age, here we found that KO mice developed adult-onset obesity. The body weight and fat mass increased significantly in KO mice compared with WT mice after 12 weeks of age. Adipocytes of KO mice were large and exhibited accumulation of triglycerides compared with WT mice. The KO mice developed obesity and insulin resistance even at a young age after consumption of high-fat/high-sucrose diet. We demonstrated the enhanced glycerol kinase enzymatic activity in Aqp7-KO and -knockdown adipocytes. A series of our results indicate that AQP7 disruption elevates adipose glycerol kinase activity, accelerates triglycerides synthesis in adipocytes, and, finally, develops obesity.
  • N Maeda; T Funahashi; T Hibuse; A Nagasawa; K Kishida; H Kuriyama; T Nakamura; S Kihara; Shimomura, I; Y Matsuzawa
    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 101 51 17801 - 17806 2004年12月 [査読有り]
     
    Adipocytes hydrolyze triglycerides and secrete free fatty acids and glycerol into the circulation. The molecular mechanism involved in glycerol transport from adipocytes has not been elucidated. Here, we investigated glycerol and glucose metabolism in mice lacking aquaporin 7 (Aqp7), a member of the aquaglyceroporins expressed in adipose tissue, and demonstrated that Aqp7 functions as a glycerol gateway molecule in vivo. Aqp7-knockout (KO) mice had lower plasma glycerol levels compared with WT mice but had normal plasma free fatty acid levels. The increase in plasma glycerol level in response to beta(3)-adrenergic agonist was severely impaired in KO mice. Epinephrine-stimulated glycerol secretion was also impaired in Aqp7 knockdown adipocytes. During prolonged fasting, plasma glycerol was elevated and the plasma glucose level was maintained in WT mice. In contrast, KO mice showed a disrupted increase of plasma glycerol and rapid reduction of plasma glucose during prolonged fasting. Our findings indicate that the lack of effective glycerol transport from adipocytes by glycerol gateway molecule causes defective adaptation to prolonged fasting.
  • M Kumada; S Kihara; N Ouchi; H Kobayashi; Y Okamoto; K Ohashi; K Maeda; H Nagaretani; K Kishida; N Maeda; A Nagasawa; T Funahashi; Y Matsuzawa
    CIRCULATION 109 17 2046 - 2049 2004年05月 [査読有り]
     
    Background - Vascular inflammation and subsequent matrix degradation play an important role in the development of atherosclerosis. We previously reported that adiponectin, an adipose-specific plasma protein, accumulated to the injured artery and attenuated vascular inflammatory response. Clinically, high plasma adiponectin level was associated with low cardiovascular event rate in patients with chronic renal failure. The present study was designed to elucidate the effects of adiponectin on matrix metalloproteinases ( MMPs) and tissue inhibitor of metalloproteinases (TIMPs) in human monocyte-derived macrophages. Methods and Results - Human monocyte-derived macrophages were incubated with the physiological concentrations of human recombinant adiponectin for the time indicated. Adiponectin treatment dose-dependently increased TIMP-1 mRNA levels without affecting MMP-9 mRNA levels. Adiponectin also augmented TIMP-1 secretion into the media, whereas MMP-9 secretion and activity were unchanged. Time course experiments indicated that TIMP-1 mRNA levels started to increase at 24 hours of adiponectin treatment and were significantly elevated at 48 hours. Adiponectin significantly increased interleukin-10 (IL-10) mRNA expression at the transcriptional level within 6 hours and significantly increased IL-10 protein secretion within 24 hours. Cotreatment of adiponectin with anti-IL-10 monoclonal antibody completely abolished adiponectin-induced TIMP-1 mRNA expression. Conclusions - Adiponectin selectively increased TIMP-1 expression in human monocyte-derived macrophages through IL-10 induction. This study identified, for the first time, the adiponectin/IL-10 interaction against vascular inflammation.
  • Koji Ohashi; Noriyuki Ouchi; Shinji Kihara; Tohru Funahashi; Tadashi Nakamura; Satoru Sumitsuji; Toshiharu Kawamoto; Satoru Matsumoto; Hiroyuki Nagaretani; Masahiro Kumada; Yoshihisa Okamoto; Hitoshi Nishizawa; Ken Kishida; Norikazu Maeda; Hisatoyo Hiraoka; Yoshio Iwashima; Kazuhiko Ishikawa; Mitsuru Ohishi; Tomohiro Katsuya; Hiromi Rakugi; Toshio Ogihara; Yuji Matsuzawa
    Journal of the American College of Cardiology 43 7 1195 - 200 2004年04月 [査読有り]
     
    OBJECTIVES: This study examined the association of mutations in adiponectin gene with the prevalence of coronary artery disease (CAD). BACKGROUND: Coronary artery disease is a major cause of mortality in the industrial countries. Adiponectin gene locus, chromosome 3q27, is the candidate site for CAD. We have reported that adiponectin has antiatherogenic and antidiabetic properties, and that the plasma levels negatively correlated with body mass index (BMI) are significantly low in patients with CAD or type 2 diabetes. METHODS: The study subjects were 383 consecutive patients with angiographically confirmed CAD and 368 non-CAD subjects adjusted for age and BMI in the Japanese population. Single nucleotide polymorphisms (SNPs) in the adiponectin gene were determined by Taqman polymerase chain reaction (PCR) method or a PCR-based assay for the analysis of restriction fragment length polymorphism. The plasma adiponectin concentration was measured by enzyme-linked immunosorbent assay. RESULTS: Among SNPs, the frequency of I164T mutation was significantly higher in CAD subjects (2.9%) than in the control (0.8%, p < 0.05). The plasma adiponectin levels in subjects carrying the I164T mutation were significantly lower than in those without the mutation, and were independent of BMI. In contrast, SNP94 and SNP276, which are reported to be associated with an increased risk of type 2 diabetes, were associated neither with CAD prevalence nor with plasma adiponectin level. Subjects with I164T mutation exhibited a clinical phenotype of the metabolic syndrome. CONCLUSIONS: The I164T mutation in the adiponectin gene was a common genetic background associated with the metabolic syndrome and CAD in the Japanese population.
  • Y Kamada; S Tamura; S Kiso; H Matsumoto; Y Saji; Y Yoshida; K Fukui; N Maeda; H Nishizawa; H Nagaretani; Y Okamoto; S Kihara; J Miyagawa; Y Shinomura; T Funahashi; Y Matsuzawa
    GASTROENTEROLOGY 125 6 1796 - 1807 2003年12月 [査読有り]
     
    Background & Aims: Obesity is one of the risk factors for liver fibrosis, in which plasma adiponectin, an adipocytokine, levels are decreased. Hepatic stellate cells play central roles in liver fibrosis. When they are activated, they undergo transformation to myofibroblast-like cells. Adiponectin suppresses the proliferation and migration of vascular smooth muscle cells, whose characteristics are similar to those of hepatic stellate cells. Adiponectin could have biological significances in liver fibrosis. Methods: The role of adiponectin on liver fibrosis induced by the administration of carbon tetrachloride twice a week for 12 weeks was tested by using adiponectin-knockout mice and an adenovirus-mediated adiponectin-expression system. We also investigated the effect of adiponectin in activated hepatic stellate cells. Results: When mice were administered carbon tetrachloride (300 muL/kg body weight) twice a week for 12 weeks, knockout mice showed extensive liver fibrosis with an enhanced expression of transforming growth factor-beta1 and connective tissue growth factor compared with wild-type mice (P < 0.05). Injection of adenovirus producing adiponectin (AdADN) before carbon tetrachloride (1000 muL/kg body weight) treatment prevented liver fibrosis in wild-type mice (P < 0.001). Injection of AdADN at 6 weeks attenuated liver fibrosis even though carbon tetrachloride was given for an additional 6 weeks (total of 12 weeks). In cultured hepatic stellate cells, adiponectin suppressed platelet-derived growth factor-induced proliferation and migration and attenuated the effect of transforming growth factor-beta1 on the gene expression of transforming growth factor-beta1 and connective tissue growth factor and on nuclear translocation of Smad2. Conclusions: The findings indicate that adiponectin attenuates liver fibrosis and could be a novel approach in its prevention.
  • A Nagasawa; K Fukui; M Kojima; K Kishida; N Maeda; H Nagaretani; T Hibuse; H Nishizawa; S Kihara; M Waki; K Takamatsu; T Funahashi; Y Matsuzawa
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 311 4 909 - 914 2003年11月 [査読有り]
     
    Adipose tissue secretes various bioactive molecules called adipocytokines. Dysregulation of adipocytokines plays an important role in the development of atherosclerotic vascular diseases. Consumption of vegetable protein reduces the risks of atherosclerotic vascular diseases. Here, we investigated the effects of 10-day dietary soy protein isolate (SPI) on the regulation of adipocytokines in Wistar rats. No significant difference in body weight was observed between SPI and Casein (animal protein) group. Expression of adipose PAI-1 was lower and expression and plasma concentration of adiponectin were higher in SPI than Casein group. Triglyceride content was lower and fatty acid synthase mRNA level in adipose tissue was lower in SPI than Casein group. Although SREBP-1 mRNA expression was decreased in the liver of SPI group, adipose SREBP and PPARgamma mRNA levels remained unchanged. Our data suggest that dietary SPI alters the gene expressions in adipose tissue and has beneficial effects on the expression of adipocytokines. (C) 2003 Elsevier Inc. All rights reserved.
  • N Ouchi; M Ohishi; S Kihara; T Funahashi; T Nakamura; H Nagaretani; M Kumada; K Ohashi; Y Okamoto; H Nishizawa; K Kishida; N Maeda; A Nagasawa; H Kobayashi; H Hiraoka; N Komai; M Kaibe; H Rakugi; T Ogihara; Y Matsuzawa
    HYPERTENSION 42 3 231 - 234 2003年09月 [査読有り]
     
    Endothelial dysfunction is a crucial feature in the evolution of atherosclerosis. Adiponectin is an adipocyte-specific plasma protein with antiatherogenic and antidiabetic properties. In the present study, we investigated the relation between adiponectin and endothelium-dependent vasodilation. We analyzed endothelial function in 202 hypertensive patients, including those who were not taking any medication. Forearm blood flow was measured by strain-gauge plethysmography. Plasma adiponectin level was highly correlated with the vasodilator response to reactive hyperemia in the total ( r = 0.257, P < 0.001) and no-medication ( r = 0.296, P = 0.026) groups but not with nitroglycerin-induced hyperemia, indicating that adiponectin affected endothelium-dependent vasodilation. Multiple regression analysis of data from all hypertensive patients revealed that plasma adiponectin level was independently correlated with the vasodilator response to reactive hyperemia. Vascular reactivity was also analyzed in aortic rings from adiponectin-knockout ( KO) and wild-type (WT) mice. Adiponectin-KO mice showed obesity, hyperglycemia, and hypertension compared with WT mice after 4 weeks on an atherogenic diet. Endothelium-dependent vasodilation in response to acetylcholine was significantly reduced in adiponectin-KO mice compared with WT mice, although no significant difference was observed in endothelium-independent vasodilation in response to sodium nitroprusside. Our observations suggest that hypoadiponectinemia is associated with impaired endothelium-dependent vasorelaxation and that the measurement of plasma adiponectin level might be helpful as a marker of endothelial dysfunction.
  • M Iwaki; M Matsuda; N Maeda; T Funahashi; Y Matsuzawa; M Makishima; Shimomura, I
    DIABETES 52 7 1655 - 1663 2003年07月 [査読有り]
     
    Adiponectin is a fat-derived hormone with antidiabetic and antiatherogenic properties. Hypoadiponectinemia seen in obesity is associated with insulin-resistant diabetes and atherosclerosis. Thiazolidinediones, peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists, have been shown to increase plasma adiponectin levels by the transcriptional induction in adipose tissues. However, the precise mechanism of such action is unknown. In this study, we have identified a functional PPAR-responsive element (PPRE) in human adiponectin promoter. PPAR-gamma/retinoid X receptor (RXR) heterodimer directly bound to the PPRE and increased the promoter activity in cells. In adipocytes, point mutation of the PPRE markedly reduced the basal transcriptional activity and completely blocked thiazolidinedione-induced transactivation of adiponectin promoter. We have also identified a responsive element of another orphan nuclear receptor, liver receptor homolog-1 (LRH-1), in adiponectin promoter. LRH-1 was expressed in 3T3-L1 cells and rat adipocytes. LRH-1 bound specifically to the identified responsive element (LRH-RE). LRH-1 augmented PPAR-gamma-induced transactivation of adiponectin promoter, and point mutation of the LRH-RE significantly decreased the basal and thiazolidinedione-induced activities of adiponectin promoter. Our results indicate that PPAR-gamma and LRH-1 play significant roles in the transcriptional activation of adiponectin gene via the PPRE and the LRH-RE in its promoter.
  • K Kishida; H Nagaretani; H Kondo; H Kobayashi; S Tanaka; N Maeda; A Nagasawa; T Hibuse; K Ohashi; M Kumada; H Nishizawa; Y Okamoto; N Ouchi; K Maeda; S Kihara; T Funahashi; Y Matsuzawa
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 306 1 286 - 292 2003年06月 [査読有り]
     
    Adiponectin, an adipocyte-derived protein, consists of collagen-like fibrous and complement C1q-like globular domains, and circulates in human plasma in a multimeric form. The protein exhibits anti-diabetic and anti-atherogenic activities. However, adiponectin plasma concentrations are low in obese subjects, and hypoadiponectinemia is associated with the metabolic syndrome, which is a cluster of insulin resistance, type 2 diabetes mellitus, hypertension, and dyslipidemia. We have recently reported a missense mutation in the adiponectin gene, in which isoleucine at position 164 in the globular domain is substituted with threonine (I164T). Subjects with this mutation showed markedly low level of plasma adiponectin and clinical features of the metabolic syndrome. Here, we examined the molecular characteristics of the mutant protein associated with a genetic cause of hypoadiponectinemia. The current study revealed (1) the mutant protein showed an oligomerization state similar to the wild-type as determined by gel filtration chromatography and, (2) the mutant protein exhibited normal insulin-sensitizing activity, but (3) pulse-chase study showed abnormal secretion of the mutant protein from adipose tissues. Our results suggest that I164T mutation is associated with hypoadiponectinemia through disturbed secretion into plasma, which may contribute to the development of the metabolic syndrome. (C) 2003 Elsevier Science (USA). All rights reserved.
  • N Ouchi; S Kihara; T Funahashi; T Nakamura; M Nishida; M Kumada; Y Okamoto; K Ohashi; H Nagaretani; K Kishida; H Nishizawa; N Maeda; H Kobayashi; H Hiraoka; Y Matsuzawa
    CIRCULATION 107 5 671 - 674 2003年02月 [査読有り]
     
    Background-High-sensitive C-reactive protein (hs-CRP) is a well-known risk factor for coronary artery disease (CAD). Recently, we have demonstrated that adiponectin served as an antiatherogenic plasma protein which was secreted specifically from adipocytes. The present study investigated the association between adiponectin and CRP in the blood stream and adipose tissue. Methods and Results-We studied a total of 101 male patients, 71 of whom had angiographically documented coronary atherosclerosis. As a control group, 30 patients with normal coronary angiogram were included. The plasma hs-CRP levels were negatively correlated with the plasma adiponectin levels (r= -0.29, P<0.01). The plasma adiponectin concentrations were significantly lower and the hs-CRP levels were significantly higher in the CAD patients compared with control subjects. The mRNA levels of CRP and adiponectin were analyzed by quantitative real-time polymerase chain reaction method. We found that the CRP mRNA was expressed in human adipose tissue. A significant inverse correlation was observed between the CRP and adiponectin mRNA levels in human adipose tissue (r=-0.89, P<0.01). In addition, the CRP mRNA level of white adipose tissue in adiponectin deficient mice was higher than that of wild-type mice. Conclusions-The reciprocal association of adiponectin and CRP levels in both human plasma and adipose tissue might participate in the development of atherosclerosis.
  • A Nagasawa; K Fukui; T Funahashi; N Maeda; Shimomura, I; S Kihara; M Waki; K Takamatsu; Y Matsuzawa
    HORMONE AND METABOLIC RESEARCH 34 11-12 635 - 639 2002年11月 [査読有り]
     
    Many studies have reported the cholesterol-lowering, anti-lipogenic, anti-obesity and anti- hypertensive effects of soy protein. Adipose tissue-specific plasma protein, adiponectin, has antiatherogenic and anti-insulin-resistance properties. Here, we investigated the effects of soy protein diet on body fat composition, plasma glucose, lipid and adiponectin levels and expression of genes involved in glucose and fatty acid metabolism in obese KK-A(y) mice. Body weights and adipose tissue weights of mesenteric, epididymal, and brown fat were lower in mice on calorie-restricted diet containing soy protein isolate. Plasma cholesterol, triglyceride, free fatty acid, and glucose levels were also decreased by this diet. Body fat content and plasma glucose levels in mice on a soy protein isolate diet were still lower than those treated with an isocaloric casein-protein-diet. Among the genes related to glucose and fatty acid metabolism, adiponectin mRNA levels in adipose tissue and adiponectin plasma concentrations were elevated in mice on a calorie-restricted diet, although there were no significant differences between soy protein and casein protein groups. Our results indicate that that soy protein diet decreased body fat content and plasma glucose levels more effectively than isocaloric casein-protein diet in obese mice.
  • Matsuda M; Shimomura I; Sata M; Arita Y; Nishida M; Maeda N; Kumada M; Okamoto Y; Nagaretani H; Nishizawa H; Kishida K; Komuro R; Ouchi N; Kihara S; Nagai R; Funahashi T; Matsuzawa Y
    The Journal of biological chemistry 277 40 37487 - 37491 2002年10月 [査読有り]
  • Role of adiponectin in preventing vascular stenosis. The missing link of adipo-vascular axis.
    Matsuda M; Shimomura I; Sata M; Arita Y; Nishida M; Maeda N; Kumada M; Okamoto Y; Nagaretani H; Nishizawa H; Kishida K; Komuro R; Ouchi N; Kihara S; Nagai R; Funahashi T; Matsuzawa Y
    J Biol Chem. 67 0 87 - 88 2002年10月 [査読有り]
  • H Kuriyama; Shimomura, I; K Kishida; H Kondo; N Furuyama; H Nishizawa; N Maeda; M Matsuda; H Nagaretani; S Kihara; T Nakamura; Y Tochino; T Funahashi; Y Matsuzawa
    DIABETES 51 10 2915 - 2921 2002年10月 [査読有り]
     
    Plasma glycerol is a major substrate for hepatic gluconeogenesis. Aquaporin adipose (AQPap/7), an adipose-specific glycerol channel, provides fat-derived glycerol into plasma. In the present study, we cloned the coding and promoter regions of mouse aquaporin 9 (AQP9), a liver-specific glycerol channel. Fasting and refeeding of mice increased and decreased hepatic AQP9 mRNA levels, respectively. Insulin deficiency induced by streptozotocin resulted in increased hepatic AQP9 mRNA. These changes in hepatic AQP9 mRNA were accompanied by those of hepatic gluconeogenic mRNAs and plasma glycerol levels. In cultured hepatocytes, insulin downregulated AQP9 mRNA. The AQP9 promoter contained the negative insulin response element TGTTTTC at -496/-502, similar to the promoter of the AQPap/7 gene. In contrast, in insulin-resistant db+/db+ mice, AQPap/7 mRNA in fat and AQP9 mRNA in liver were increased, despite hyperinsulinemia, with high plasma glycerol and glucose levels. Glycerol infusion in the db+/db+ mice augmented hepatic glucose output. Our results indicate that coordinated regulations of fat-specific AQPap/7 and liver-specific AQP9 should be crucial to determine glucose metabolism in physiology and insulin resistance.
  • H Nishizawa; H Shimomura; K Kishida; N Maeda; H Kuriyama; H Nagaretani; M Matsuda; H Kondo; N Furuyama; S Kihara; T Nakamura; Y Tochino; T Funahashi; Y Matsuzawa
    DIABETES 51 9 2734 - 2741 2002年09月 [査読有り]
     
    Adiponectin, an adipose-specific secretory protein, exhibits antidiabetic and antiatherogenic properties. In the present study, we examined the effects of sex hormones on the regulation of adiponectin production. Plasma adiponectin concentrations were significantly lower in 442 men (age, 52.6 +/- 11.9 years [mean +/- SD]) than in 137 women (53.2 +/- 12.0 years) but not different between pre- and postmenopausal women. In mice, ovariectomy did not alter plasma adiponectin levels. In contrast, high levels of plasma adiponectin were found in castrated mice. Testosterone treatment reduced plasma adiponectin concentration in both sham-operated and castrated mice. In 3T3-L1 adipocytes, testosterone reduced adiponectin secretion into the culture media, using pulse-chase study. Castration-induced increase in plasma adiponectin was associated with a significant improvement of insulin sensitivity. Our results indicate that androgens decrease plasma adiponectin and that androgen-induced hypoadiponectinemia may be related to the high risks of insulin resistance and atherosclerosis in men.
  • N Maeda; Shimomura, I; K Kishida; H Nishizawa; M Matsuda; H Nagaretani; N Furuyama; H Kondo; M Takahashi; Y Arita; R Komuro; N Ouchi; S Kihara; Y Tochino; K Okutomi; M Horie; S Takeda; T Aoyama; T Funahashi; Y Matsuzawa
    NATURE MEDICINE 8 7 731 - 737 2002年07月 [査読有り]
     
    Here we investigated the biological functions of adiponectin/ACRP30, a fat-derived hormone, by disrupting the gene that encodes it in mice. Adiponectin/ACRP30-knockout (KO) mice showed delayed clearance of free fatty acid in plasma, low levels of fatty-acid transport protein 1 (FATP-1) mRNA in muscle, high levels of tumor necrosis factor-alpha (TNF-alpha) mRNA in adipose tissue and high plasma TNF-alpha concentrations. The KO mice exhibited severe diet-induced insulin resistance with reduced insulin-receptor substrate 1 (IRS-1)-associated phosphatidylinositol 3 kinase (PI3-kinase) activity in muscle. Viral mediated adiponectin/ACRP30 expression in KO mice reversed the reduction of FATP-1 mRNA, the increase of adipose TNF-alpha mRNA and the diet-induced insulin resistance. In cultured myocytes, TNF-alpha decreased FATP-1 mRNA, IRS-1-associated PI3-kinase activity and glucose uptake, whereas adiponectin increased these parameters. Our results indicate that adiponectin/ACRP30 deficiency and high TNF-alpha levels in KO mice reduced muscle FATP-1 mRNA and IRS-1-mediated insulin signaling, resulting in severe diet-induced insulin resistance.
  • S Matsumoto; K Kishida; Shimomura, I; N Maeda; H Nagaretani; M Matsuda; H Nishizawa; S Kihara; T Funahashi; Y Matsuzawa
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 292 3 781 - 786 2002年04月 [査読有り]
     
    The mechanism by which the obese subjects are more associated with vascular disease remains unclear. We reported that the adipose tissues produce and secrete many bioactive molecules, conceptualized as adipocytokines. Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), produced locally by vascular macrophages and smooth muscle cells, has been suggested to induce the migration and proliferation of vascular smooth muscle cells. The current study reveals that (1) HB-EGF mRNA is abundantly expressed in human adipose tissue, (2) HB-EGF mRNA increases in the fat tissues of obese mice, (3) plasma HB-EGF levels increase in parallel with fat accumulation in human, and (4) the subjects with coronary artery disease have higher plasma HB-EGF levels, associated with fat accumulation. These results suggest that increased plasma HB-EGF derived from the accumulated fat contributes to the higher incidence of vascular disease in obesity, proposing HB-EGF as an adipocytokine directly linking adipovascular axis. (C) 2002 Elsevier Science (USA).
  • H Kondo; Shimomura, I; K Kishida; H Kuriyama; Y Makino; H Nishizawa; M Matsuda; N Maeda; H Nagaretani; S Kihara; Y Kurachi; T Nakamura; T Funahashi; Y Matsuzawa
    EUROPEAN JOURNAL OF BIOCHEMISTRY 269 7 1814 - 1826 2002年04月 [査読有り]
     
    Aquaporin adipose (AQPap), which we identified from human adipose tissue, is a glycerol channel in adipocyte [Kishida et al. (2000) J. Biol. Chem. 275, 20896-20902]. In the current study, we determined the genomic structure of the human AQPap gene, and identified three AQPap-like genes that resembled (approximate to 95%) AQPap, with little expression in human tissues. The AQPap promoter contained a putative peroxisome proliferator response element (PPRE) at -46 to -62, and a putative insulin response element (IRE) at -542/-536. Deletion of the PPRE abolished the pioglitazone-mediated induction of AQPap promoter activity in 3T3-L1 adipocytes. Deletion and single base pair substitution analysis of the IRE abolished the insulin-mediated suppression of the human AQPap gene. Analysis of AQPap sequence in human subjects revealed three missense mutations (R12C, V59L and G264V), and two silent mutations (A103A and G250G). The cRNA injection of the missense mutants into Xenopus oocytes revealed the absence of the activity to transport glycerol and water in the AQPap-G264V protein. In the subject homozygous for AQPap-G264V, exercise-induced increase in plasma glycerol was not observed in spite of the increased plasma noradrenaline. We suggest that AQPap is responsible for the increase of plasma glycerol during exercise in humans.
  • H Nishizawa; K Yamagata; L Shimomura; M Takahashi; H Kuriyama; K Kishida; K Hotta; H Nagaretani; N Maeda; M Matsuda; S Kihara; T Nakamura; H Nishigori; H Tomura; DD Moore; J Takeda; T Funahashi; Y Matsuzawa
    JOURNAL OF BIOLOGICAL CHEMISTRY 277 2 1586 - 1592 2002年01月 [査読有り]
     
    Small heterodimer partner (SHP, NR0B2) is an atypical orphan nuclear receptor that inhibits transcriptional activation by several other nuclear receptors. We recently reported that mutations in the SHP gene are associated with insulin resistance. In the present study, we demonstrated that the SHP gene is expressed in adipose tissues. A reporter gene assay showed that a gene product of SHP increased the transcriptional activation of peroxisome proliferator-activated receptor (PPAR) gamma. SHP-mediated activation of PPARgamma was observed both in the presence and absence of the ligand of PPARgamma. Immunoprecipitation and glutathione S-transferase pull-down assay showed that SHP directly bound to PPARgamma and competed with nuclear receptor corepressor for binding to PPARgamma. Serial deletion studies indicated that the C terminus of SHP is important for PPARgamma activation. Mutant SHP proteins, which are found in naturally occurring mutation, showed less enhancing activity for PPARgamma than wild-type SHP. Our results suggest that SHP may act as an endogenous enhancer of PPARgamma.
  • Kishida K; Shimomura I; Nishizawa H; Maeda N; Kuriyama H; Kondo H; Matsuda M; Nagaretani H; Ouchi N; Hotta K; Kihara S; Kadowaki T; Funahashi T; Matsuzawa Y
    Journal of Biological Chemistry 276 51 48572 - 48579 2001年12月 [査読有り]
  • K Kishida; Shimomura, I; H Kondo; H Kuriyama; Y Makino; H Nishizawa; N Maeda; M Matsuda; N Ouchi; S Kihara; Y Kurachi; T Funahashi; Y Matsuzawa
    JOURNAL OF BIOLOGICAL CHEMISTRY 276 39 36251 - 36260 2001年09月 [査読有り]
     
    In the current study, we examined the genomic structure of the mouse AQPap gene and its regulation by insulin. The mouse AQPap gene spanned 12 kilobase pairs in chromosome 4 and consisted of 8 exons and 7 introns. The first two exons, designated exon I and exon 1', are alternatively spliced to common exon 2, and thus the AQPap gene possessed two potential promoters. The exon 1-derived transcript is dominant in both adipose tissues and adipocytes on the basis of RNase protection assay and promoter analysis. The mRNA increased after fasting and decreased with refeeding. Insulin deficiency generated by streptozotocin enhanced the mRNA in adipose tissue. Insulin down-regulated AQPap mRNA in 3T3-L1 adipocytes. The AQPap promoter contained heptanucleotide sequences, TGTTTTT at -443/-437, similar to the insulin-response element identified previously in the promoters of insulin-repressed genes. Deletion and single base pair substitution analysis of the promoter revealed that these sequences were required for insulin-mediated repression of AQPap gene transcription. The phosphatidylinositol 3-kinase pathway was involved in this inhibition. We conclude that insulin represses the transcription of AQPap gene via insulin response element in its promoter. Sustained up-regulation of AQPap mRNA in adipose tissue in the insulin-resistant condition may disturb glucose homeostasis by increasing plasma glycerol.
  • N Maeda; M Takahashi; T Funahashi; S Kihara; H Nishizawa; K Kishida; H Nagaretani; M Matsuda; R Komuro; N Ouchi; H Kuriyama; K Hotta; T Nakamura; Shimomura, I; Y Matsuzawa
    DIABETES 50 9 2094 - 2099 2001年09月 [査読有り]
     
    Insulin resistance and its dreaded consequence, type 2 diabetes, are major causes of atherosclerosis. Adiponectin is an adipose-specific plasma protein that possesses anti-atherogenic properties, such as the suppression of adhesion molecule expression in vascular endothelial cells and cytokine production from macrophages. Plasma adiponectin concentrations are decreased in obese and type 2 diabetic subjects with insulin resistance. A regimen that normalizes or increases the plasma adiponectin might prevent atherosclerosis in patients with insulin resistance. In this study, we demonstrate the inducing effects of thiazolidinediones (TZDs), which are synthetic PPAR gamma ligands, on the expression and secretion of adiponectin in humans and rodents in vivo and in vitro. The administration of TZDs significantly increased the plasma adiponectin concentrations in insulin resistant humans and rodents without affecting their body weight. Adiponectin mRNA expression was normalized or increased by TZDs in the adipose tissues of obese mice. In cultured 3T3-L1 adipocytes, TZD derivatives enhanced the mRNA expression and secretion of adiponectin in a dose- and time-dependent manner. Furthermore, these effects were mediated through the activation of the promoter by the TZDs. On the other hand, TNF-a, which is produced more in an insulin-resistant condition, dose-dependently reduced the expression of adiponectin in adipocytes by suppressing its promoter activity. TZDs restored this inhibitory effect by TNF-alpha. TZDs might prevent atherosclerotic vascular disease in insulin-resistant patients by inducing the production of adiponectin through direct effect on its promoter and antagonizing the effect of TNF-alpha on the adiponectin promoter.
  • Takahashi M; Nagaretani H; Funahashi T; Nishizawa H; Maeda N; Kishida K; Kuriyama H; Shimomura I; Maeda K; Hotta K; Ouchi N; Kihara S; Nakamura T; Yamashita S; Matsuzawa Y
    Obes Res 9 7 388 - 393 2001年07月 [査読有り]
  • O Yasuda; K Fukuo; N Maeda; T Ogihara
    ATHEROSCLEROSIS VI 947 312 - 315 2001年 [査読有り]
     
    The proliferation of smooth muscle cells (SMCs) is a key event in the development of atherosclerosis. To compare the nature of SMCs from advanced atherosclerotic lesions and normal aortic segments, we established SMC lines from plaque-containing portions (P) and non-plaque portions (NP) of aortas of apolipoprotein-E-deficient mice. Differential display showed several transcripts that were differentially expressed in P and NP lines. One of the transcripts whose expression was elevated in P lines compared to their NP counterparts was for type VIII collagen. Type VIII collagen transcripts were also readily detectable by RT-PCR in RNA isolated from plaques freshly dissected from apolipoprotein-E-deficient mice, but not in RNA Isolated from the normal part of the aorta or from adventitia. In situ hybridization showed localization of Col8alpha1 transcripts near the luminal surface of the plaque. Thus, differential production of type VIII collagen in SMCs from atherosclerotic plaques continues when the cells are maintained in culture.
  • Kishida K; Shimomura I (co; s; onde; u; Kondo H; Kuriyama H; Makino Y; Nishizawa H; Maeda N; Matsuda M; Ouchi N; Kihara S; Kurachi Y; Funahashi T; Matsuzawa Y
    Journal of Biological Chemistry 276 39 36251 - 36260 2001年 [査読有り]
  • Norikazu Maeda; Hisatoyo Hiraoka; Tadashi Nakamura; Fumihiko Matsuura; Noriyuki Ouchi; Atsuyuki Nakata; Hitoshi Kobayashi; Shizuya Yamashita; Kaoru Kameda-Takemura; Yuji Matsuzawa; Tadashi Nakamura
    Angiology 48 11 995 - 999 1997年11月 [査読有り]
     
    We demonstrated a continuous intracoronary infusion of acetylcholine-induced marked decrease of coronary blood flow estimated by intracoronary Doppler flow wire without significant epicardial coronary narrowing. This case can be called a patient with microvas cular vasospastic angina.

書籍

講演・口頭発表等

MISC

  • 馬場谷成; 能宗伸輔; 廣峰義久; 武友保憲; 庭野史丸; 吉田左和; 安武紗良; 川畑由美子; 池上博司; 前田法一 日本内分泌学会雑誌 99 (2) 635 2023年10月
  • 前田法一 皮膚病診療 45 (10) 848 -856 2023年10月 [査読有り]
  • 鍵崎卓也; 川知祐介; 向井康祐; 宮下和幸; 小澤純二; 前田法一; 大橋勇紀; 市田公美; 西澤均; 下村伊一郎 日本内分泌学会雑誌 99 (1) 390 -390 2023年05月
  • 藤島裕也; 西澤均; 川知祐介; 原知之; 村瀬貴代; 赤利精悟; 中村敬志; 渡邉裕尭; 田矢直大; 高原均; 片上充佳; 前田法一; 中田研; 下村伊一郎 日本内分泌学会雑誌 99 (1) 385 -385 2023年05月
  • 藤井浩平; 藤島裕也; 福田士郎; 喜多俊文; 西澤均; 前田法一; 下村伊一郎 日本内分泌学会雑誌 99 (1) 383 -383 2023年05月
  • 田村有里; 川知祐介; 藤島裕也; 向井康祐; 宮下和幸; 西澤均; 前田法一; 福原淳範; 下村伊一郎 日本内分泌学会雑誌 99 (1) 362 -362 2023年05月
  • 川知祐介; 藤島裕也; 赤利精悟; 中村敬志; 西澤均; 前田法一; 星出聡; 苅尾七臣; 下村伊一郎 日本内分泌学会雑誌 99 (1) 343 -343 2023年05月
  • 早川友朗; 向井康祐; 宮下和幸; 小澤純二; 片上直人; 西澤均; 前田法一; 福原淳範; 大月道夫; 下村伊一郎 日本内分泌学会雑誌 99 (1) 319 -319 2023年05月
  • 馬殿恵; 加藤更紗; 仁木暁子; 満塩研人; 原知之; 木村優; 川知祐介; 小澤栄稔; 石橋千咲; 細川吉弥; 藤田有可里; 藤島裕也; 徳永あゆみ; 南茂隆生; 小澤純二; 西澤均; 前田法一; 下村伊一郎 日本内分泌学会雑誌 99 (1) 212 -212 2023年05月
  • 木村優; 藤島裕也; 徳澤千恵; 西澤均; 白波瀬景子; 竹治香菜; 山口智勢; 長井直子; 川知祐介; 福田士郎; 喜多俊文; 西塔拓郎; 宮崎安弘; 前田和久; 前田法一; 土岐祐一郎; 下村伊一郎 日本内分泌学会雑誌 99 (1) 296 -296 2023年05月
  • 沖田朋憲; 喜多俊文; 福田士郎; 福岡啓太; 堀谷恵美; 飯岡雅仁; 藤島裕也; 西澤均; 前田法一; 下村伊一郎 日本内分泌学会雑誌 99 (1) 286 -286 2023年05月
  • 嶺尾良平; 鈴木茂仁; 伊藤慶人; 丹波祥子; 杉山拓也; 山本浩司; 福田士郎; 藤島裕也; 西澤均; 前田法一; 下村伊一郎; 松澤佑次 糖尿病 66 (Supplement1) S-255 -S-255 2023年04月
  • 馬殿恵; 加藤更紗; 仁木暁子; 満塩研人; 原知之; 木村優; 川知祐介; 小澤栄稔; 石橋千咲; 細川吉弥; 藤田有可里; 藤島裕也; 徳永あゆみ; 南茂隆生; 小澤純二; 西澤均; 前田法一; 下村伊一郎 糖尿病 66 (Supplement1) S-241 -S-241 2023年04月
  • 原知之; 藤島裕也; 川知祐介; 福田士郎; 木村優; 島田香菜; 山口智勢; 徳澤千恵; 長井直子; 喜多俊文; 西澤均; 前田法一; 下村伊一郎 糖尿病 66 (Supplement1) S-211 -S-211 2023年04月
  • 坂上貴章; 藤島裕也; 福嶋葉子; 清水有理; 福田士郎; 喜多俊文; 西澤均; 西田幸二; 前田法一; 下村伊一郎 糖尿病 66 (Supplement1) S-146 -S-146 2023年04月
  • 太田滋之; 堀谷恵美; 喜多俊文; 沖田朋憲; 倉田隼人; 西田浩之; 本間陽一; 小澤純二; 東みゆき; 福田士郎; 藤島裕也; 西澤均; 前田法一; 下村伊一郎 糖尿病 66 (Supplement1) S-152 -S-152 2023年04月
  • 福田士郎; 飯岡雅仁; 河田慶太郎; 藤井浩平; 福岡啓太; 堀谷恵美; 坂上貴章; 川知祐介; 沖田朋憲; 藤島裕也; 喜多俊文; 西澤均; 前田法一; 下村伊一郎 糖尿病 66 (Supplement1) S-273 -S-273 2023年04月
  • 藤島裕也; 喜多俊文; 西澤均; 前田法一; 下村伊一郎 糖尿病 66 (Supplement1) S-29 -S-29 2023年04月
  • 太田滋之; 太田滋之; 堀谷恵美; 喜多俊文; 喜多俊文; 沖田朋憲; 倉田隼人; 西田浩之; 本間陽一; 小澤純二; 小澤純二; 東みゆき; 福田士郎; 藤島裕也; 西澤均; 前田法一; 前田法一; 下村伊一郎 糖尿病(Web) 66 (Suppl) 2023年
  • 肝酵素上昇患者の血管進展性指標に対するXOR阻害薬(トピロキソスタット)の影響 BEYOND-UA studyサブ解析
    西澤 均; 川知 祐介; 赤利 精悟; 中村 敬志; 藤島 裕也; 前田 法一; 下村 伊一郎; 星出 聡; 苅尾 七臣 日本痛風・尿酸核酸学会総会プログラム・抄録集 56回 96 -96 2023年01月
  • アディポネクチン
    前田 法一 日本臨床生理学会雑誌 52 (3) 121 -127 2022年08月
  • 123I-MIBGの高集積を認め褐色細胞腫を疑った散発性副腎髄質過形成の1例
    脇田 哲平; 波多野 浩士; 堀谷 弘; 竹澤 健太郎; 福原 慎一郎; 藤田 和利; 植村 元秀; 木内 寛; 今村 亮一; 野々村 祝夫; 前田 法一; 西澤 均; 向井 康祐; 大月 道夫 泌尿器科紀要 68 (8) 282 -282 2022年08月
  • 動脈硬化症とメタボリックシンドローム 内臓脂肪蓄積に基づく動脈硬化発症起点
    前田 法一; 下村 伊一郎 日本動脈硬化学会総会プログラム・抄録集 54回 126 -126 2022年07月
  • 非アルコール性脂肪性肝疾患(NAFLD)における血中XOR活性の上昇と、その血管障害への関与
    川知 祐介; 藤島 裕也; 西澤 均; 中村 敬志; 赤利 精悟; 村瀬 貴代; 西塔 拓郎; 宮崎 安弘; 喜多 俊文; 土岐 祐一郎; 前田 法一; 下村 伊一郎 メタボリックシンドローム 17 (1) 24 -27 2022年06月
  • 非アルコール性脂肪性肝疾患(NAFLD)における血中XOR活性の上昇と、その血管障害への関与
    川知 祐介; 藤島 裕也; 西澤 均; 中村 敬志; 赤利 精悟; 村瀬 貴代; 西塔 拓郎; 宮崎 安弘; 喜多 俊文; 土岐 祐一郎; 前田 法一; 下村 伊一郎 メタボリックシンドローム 17 (1) 24 -27 2022年06月
  • 免疫チェックポイント阻害薬投与により誘発される1型糖尿病への間葉系幹細胞投与効果の検討
    堀谷 恵美; 喜多 俊文; 沖田 朋憲; 中村 勇斗; 西田 浩之; 本間 陽一; 小澤 純二; 東 みゆき; 前田 法一; 下村 伊一郎 日本内分泌学会雑誌 98 (1) 359 -359 2022年04月
  • 免疫チェックポイント阻害薬投与により誘発される1型糖尿病への間葉系幹細胞投与効果の検討
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  • 異所性受容体発現を評価した軽度高血圧合併PMAH(Primary Macronodular Adrenal Hyperplasia)の一症例
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  • インスリン投与が有用であった著明な高中性脂肪血症を呈したAPOA5遺伝子複合ヘテロ変異を持つ糖尿病症例
    博多 紗弓; 藤田 真吾; 宮下 和幸; 向井 康祐; 小澤 純二; 前田 法一; 西澤 均; 下村 伊一郎 糖尿病 65 (Suppl.1) S -260 2022年04月
  • エクソーム解析にて稀少なLPL遺伝子複合ヘテロ変異が明らかとなった高中性脂肪血症例
    園浦 望美; 藤田 真吾; 宮下 洋平; 宮下 和幸; 向井 康祐; 朝野 仁裕; 小澤 純二; 前田 法一; 西澤 均; 下村 伊一郎 糖尿病 65 (Suppl.1) S -261 2022年04月
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  • 可溶性T-カドヘリンはNotchシグナルの増幅を介して膵β細胞の増殖を促進する
    沖田 朋憲; 喜多 俊文; 福田 士郎; 福岡 啓太; 堀谷 恵美; 藤島 裕也; 西澤 均; 前田 法一; 下村 伊一郎 日本内分泌学会雑誌 98 (1) 271 -271 2022年04月
  • 肝由来XORの病態学的意義 NAFLD/NASH病態における動脈硬化症への関与
    川知 祐介; 藤島 裕也; 西澤 均; 中村 敬志; 赤利 精悟; 村瀬 貴代; 西塔 拓郎; 宮崎 安弘; 喜多 俊文; 土岐 祐一郎; 前田 法一; 下村 伊一郎 日本内分泌学会雑誌 98 (1) 272 -272 2022年04月
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    喜多 俊文; 福田 士郎; 沖田 朋憲; 堀谷 恵美; 福岡 啓太; 河田 慶太郎; 飯岡 雅仁; 藤井 浩平; 中村 勇斗; 清水 有理; 坂上 貴章; 藤島 裕也; 西澤 均; 前田 法一; 下村 伊一郎 日本内分泌学会雑誌 98 (1) 359 -359 2022年04月
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    福岡 啓太; 喜多 俊文; 嶺尾 良平; 福田 士郎; 沖田 朋憲; 堀谷 恵美; 河田 慶太郎; 飯岡 雅仁; 藤井 浩平; 中村 勇斗; 清水 有理; 坂上 貴章; 藤島 裕也; 西澤 均; 前田 法一; 下村 伊一郎 日本内分泌学会雑誌 98 (1) 394 -394 2022年04月
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    飯岡 雅仁; 福田 士郎; 夏川 知輝; 澤野 宏隆; 藤島 裕也; 喜多 俊文; 西澤 均; 前田 法一; 下村 伊一郎 日本内分泌学会雑誌 98 (1) 394 -394 2022年04月
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    馬殿 恵; 仁木 暁子; 満塩 研人; 原 知之; 川知 祐介; 堀井 知美; 石橋 千咲; 藤田 真吾; 藤田 有可里; 藤島 裕也; 木村 武量; 徳永 あゆみ; 南茂 隆生; 小澤 純二; 西澤 均; 前田 法一; 下村 伊一郎 糖尿病 65 (Suppl.1) S -145 2022年04月
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    木村 優; 藤島 裕也; 徳澤 千恵; 西澤 均; 白波瀬 景子; 竹治 香菜; 山口 智勢; 長井 直子; 川知 祐介; 福田 士郎; 喜多 俊文; 西塔 拓郎; 宮崎 安弘; 前田 和久; 前田 法一; 土岐 祐一郎; 下村 伊一郎 糖尿病 65 (Suppl.1) S -153 2022年04月
  • 新たな食嗜好質問表の作成と肥満2型糖尿病患者での評価
    原 知之; 藤島 裕也; 川知 祐介; 福田 士郎; 木村 優; 竹治 香菜; 山口 智勢; 徳澤 千恵; 長井 直子; 喜多 俊文; 西澤 均; 前田 法一; 下村 伊一郎 糖尿病 65 (Suppl.1) S -197 2022年04月
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    坂上 貴章; 藤島 裕也; 福嶋 葉子; 清水 有理; 福田 士郎; 喜多 俊文; 西澤 均; 西田 幸二; 前田 法一; 下村 伊一郎 糖尿病 65 (Suppl.1) S -215 2022年04月
  • 可溶性T-カドヘリンはNotchシグナルの増幅を介して膵β細胞の増殖を促進する
    沖田 朋憲; 喜多 俊文; 福田 士郎; 福岡 啓太; 堀谷 恵美; 藤島 裕也; 西澤 均; 前田 法一; 下村 伊一郎 糖尿病 65 (Suppl.1) S -216 2022年04月
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    福田 士郎; 飯岡 雅仁; 村井 潤; 中村 正; 堀谷 恵美; 坂上 貴章; 川知 祐介; 沖田 朋憲; 清水 有理; 藤島 裕也; 喜多 俊文; 西澤 均; 前田 法一; 下村 伊一郎 糖尿病 65 (Suppl.1) S -252 2022年04月
  • 清水 有理; 木村 武量; 上間 遼太郎; 新崎 信一郎; 小澤 純二; 前田 法一; 岩橋 博見; 今川 彰久; 下村 伊一郎 日本内分泌学会雑誌 98 (1) 404 -404 2022年04月
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    堀谷 恵美; 喜多 俊文; 沖田 朋憲; 中村 勇斗; 西田 浩之; 本間 陽一; 小澤 純二; 東 みゆき; 前田 法一; 下村 伊一郎 糖尿病 65 (Suppl.1) S -130 2022年04月
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    馬殿 恵; 仁木 暁子; 満塩 研人; 原 知之; 川知 祐介; 堀井 知美; 石橋 千咲; 藤田 真吾; 藤田 有可里; 藤島 裕也; 木村 武量; 徳永 あゆみ; 南茂 隆生; 小澤 純二; 西澤 均; 前田 法一; 下村 伊一郎 糖尿病 65 (Suppl.1) S -145 2022年04月
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    原 知之; 藤島 裕也; 川知 祐介; 福田 士郎; 木村 優; 竹治 香菜; 山口 智勢; 徳澤 千恵; 長井 直子; 喜多 俊文; 西澤 均; 前田 法一; 下村 伊一郎 糖尿病 65 (Suppl.1) S -197 2022年04月
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    坂上 貴章; 藤島 裕也; 福嶋 葉子; 清水 有理; 福田 士郎; 喜多 俊文; 西澤 均; 西田 幸二; 前田 法一; 下村 伊一郎 糖尿病 65 (Suppl.1) S -215 2022年04月
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    沖田 朋憲; 喜多 俊文; 福田 士郎; 福岡 啓太; 堀谷 恵美; 藤島 裕也; 西澤 均; 前田 法一; 下村 伊一郎 糖尿病 65 (Suppl.1) S -216 2022年04月
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    福田 士郎; 飯岡 雅仁; 村井 潤; 中村 正; 堀谷 恵美; 坂上 貴章; 川知 祐介; 沖田 朋憲; 清水 有理; 藤島 裕也; 喜多 俊文; 西澤 均; 前田 法一; 下村 伊一郎 糖尿病 65 (Suppl.1) S -252 2022年04月
  • インスリン投与が有用であった著明な高中性脂肪血症を呈したAPOA5遺伝子複合ヘテロ変異を持つ糖尿病症例
    博多 紗弓; 藤田 真吾; 宮下 和幸; 向井 康祐; 小澤 純二; 前田 法一; 西澤 均; 下村 伊一郎 糖尿病 65 (Suppl.1) S -260 2022年04月
  • エクソーム解析にて稀少なLPL遺伝子複合ヘテロ変異が明らかとなった高中性脂肪血症例
    園浦 望美; 藤田 真吾; 宮下 洋平; 宮下 和幸; 向井 康祐; 朝野 仁裕; 小澤 純二; 前田 法一; 西澤 均; 下村 伊一郎 糖尿病 65 (Suppl.1) S -261 2022年04月
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    沖田 朋憲; 喜多 俊文; 福田 士郎; 福岡 啓太; 堀谷 恵美; 藤島 裕也; 西澤 均; 前田 法一; 下村 伊一郎 日本内分泌学会雑誌 98 (1) 271 -271 2022年04月
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    早川 友朗; 向井 康祐; 宮下 和幸; 小澤 純二; 片上 直人; 西澤 均; 前田 法一; 福原 淳範; 大月 道夫; 下村 伊一郎 日本内分泌学会雑誌 98 (1) 272 -272 2022年04月
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    堀谷 恵美; 喜多 俊文; 沖田 朋憲; 中村 勇斗; 西田 浩之; 本間 陽一; 小澤 純二; 東 みゆき; 前田 法一; 下村 伊一郎 日本内分泌学会雑誌 98 (1) 359 -359 2022年04月
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    清水 有理; 木村 武量; 上間 遼太郎; 新崎 信一郎; 小澤 純二; 前田 法一; 岩橋 博見; 今川 彰久; 下村 伊一郎 日本内分泌学会雑誌 98 (1) 404 -404 2022年04月
  • 管理栄養士と医師が相互理解しながら、患者さんを多方面からサポートするには? 減量・代謝改善手術による食行動の変化と、術後体重減少との関連性
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  • 管理栄養士と医師が相互理解しながら、患者さんを多方面からサポートするには? 「食行動質問表」を用いた高度肥満症患者の栄養食事指導の実際
    長井 直子; 西澤 均; 藤島 裕也; 山口 智勢; 徳澤 千恵; 木村 優; 福田 士郎; 西塔 拓郎; 前田 法一; 土岐 祐一郎; 下村 伊一郎 肥満研究 27 (Suppl.) 254 -254 2022年03月
  • 新たな食嗜好質問表の作成と肥満症患者での評価
    原 知之; 徳澤 千恵; 藤島 裕也; 木村 優; 川知 祐介; 福田 士郎; 山口 智勢; 白波瀬 景子; 西塔 拓郎; 長井 直子; 西澤 均; 前田 法一; 下村 伊一郎 肥満研究 27 (Suppl.) 290 -290 2022年03月
  • アディポネクチンと血中T-カドヘリン 新たな分泌因子相互作用機構の観点から
    福田 士郎; 喜多 俊文; 飯岡 雅仁; 福岡 啓太; 沖田 朋憲; 清水 有理; 藤島 裕也; 西澤 均; 前田 法一; 下村 伊一郎 肥満研究 27 (Suppl.) 344 -344 2022年03月
  • アディポネクチンと血中T-カドヘリン 新たな分泌因子相互作用機構の観点から
    福田 士郎; 喜多 俊文; 飯岡 雅仁; 福岡 啓太; 沖田 朋憲; 清水 有理; 藤島 裕也; 西澤 均; 前田 法一; 下村 伊一郎 肥満研究 27 (Suppl.) 344 -344 2022年03月
  • 前田 法一 日本内分泌学会雑誌 97 (2) 472 -472 2021年10月
  • 肥満と健康障害 メタボリックシンドロームの新たな病態基盤
    前田 法一 日本臨床生理学会雑誌 51 (4) 48 -48 2021年10月
  • アディポネクチンのT-cadherinを介した血管周皮細胞への集積と腎保護作用
    清水 有理; 藤島 裕也; 喜多 俊文; 南 聡; 坂上 貴章; 中村 勇斗; 堀谷 恵美; 沖田 朋憲; 川知 祐介; 福田 士郎; 難波 倫子; 高畠 義嗣; 猪阪 善隆; 西澤 均; 前田 法一; 下村 伊一郎 糖尿病 64 (Suppl.1) YIA -3) 2021年05月
  • オクトレオチド投与後に低血糖改善効果が得られなかったインスリノーマの一例 ソマトスタチン受容体発現の組織学的検討を含めて
    満塩 研人; 石橋 千咲; 藤田 真吾; 米田 祥; 藤田 有可里; 南茂 隆生; 坂本 紗英花; 籠田 芳夫; 飯岡 雅仁; 木村 武量; 福井 健司; 宮下 一幸; 西澤 均; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝昭; 江口 英利; 下村 伊一郎 糖尿病 64 (Suppl.1) I -1 2021年05月
  • ステロイド治療中に早朝低血糖で救急搬送された重症筋無力症の1例
    石橋 千咲; 原 知之; 向井 康祐; 木村 武量; 福井 健司; 宮下 和幸; 西澤 均; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝昭; 下村 伊一郎 糖尿病 64 (Suppl.1) I -2 2021年05月
  • デキストロメトルファンによって生じたと考えられる低血糖の1例
    鈴木 茂仁; 木村 武量; 石橋 千咲; 福井 健司; 宮下 和幸; 西澤 均; 小澤 純二; 片上 直人; 前田 法一; 大月 道夫; 下村 伊一郎 糖尿病 64 (Suppl.1) I -4 2021年05月
  • 膵多血性腫瘍と反応性低血糖を認めた一例
    木村 武量; 飯岡 正仁; 西澤 均; 小澤 純二; 片上 直人; 前田 法一; 大月 道夫; 下村 伊一郎 糖尿病 64 (Suppl.1) I -5 2021年05月
  • 全エクソーム解析にてMODY3が明らかとなった若年発症インスリン分泌低下型糖尿病一家系
    森 由希子; 藤田 真吾; 宮下 洋平; 石橋 千咲; 南茂 隆生; 宮下 和幸; 西澤 均; 前田 法一; 大月 道夫; 松岡 孝昭; 朝野 仁裕; 小澤 純二; 下村 伊一郎 糖尿病 64 (Suppl.1) III -3 2021年05月
  • 2番染色体p25.3部欠失が原因と考えられた遺伝性肥満の一例
    坂上 貴章; 小幡 佳也; 藤島 裕也; 小澤 純二; 西澤 均; 松岡 孝昭; 岩橋 博見; 前田 法一; 大月 道夫; 山本 俊至; 下村 伊一郎 糖尿病 64 (Suppl.1) III -5 2021年05月
  • 間葉系幹細胞による新規糖尿病治療に対する検討
    堀谷 恵美; 喜多 俊文; 中村 勇斗; 秦 誠倫; 沖田 朋憲; 福田 士郎; 藤島 裕也; 西澤 均; 前田 法一; 下村 伊一郎 糖尿病 64 (Suppl.1) P -6 2021年05月
  • 生理的血中アディポネクチンの結合解析
    喜多 俊文; 福田 士郎; 中村 勇斗; 沖田 朋憲; 堀谷 恵美; 清水 有理; 川知 祐介; 坂上 貴章; 秦 誠倫; 飯岡 雅仁; 藤島 裕也; 西澤 均; 前田 法一; 下村 伊一郎 糖尿病 64 (Suppl.1) P -2 2021年05月
  • 免疫チェックポイント阻害薬投与後に緩徐なインスリン分泌低下を来した糖尿病症例の一例
    福井 健司; 森 由希子; 石橋 千咲; 木村 武量; 宮下 和幸; 西澤 均; 前田 法一; 大月 道夫; 小澤 純二; 下村 伊一郎 糖尿病 64 (Suppl.1) P -7 2021年05月
  • ヒト血中可溶型T-カドヘリンの存在様式の解明と測定系の確立
    福田 士郎; 飯岡 雅仁; 宮下 かずや; 堀谷 恵美; 坂上 貴章; 川知 祐介; 沖田 朋憲; 清水 有理; 藤島 裕也; 喜多 俊文; 西澤 均; 前田 法一; 下村 伊一郎 糖尿病 64 (Suppl.1) P -2 2021年05月
  • アディポネクチンは間葉系幹細胞のエクソソーム産生を促進させることでマクロファージのM2分極化を促進する
    沖田 朋憲; 喜多 俊文; 堀谷 恵美; 福田 士郎; 川知 祐介; 清水 有理; 藤島 裕也; 西澤 均; 前田 法一; 下村 伊一郎 糖尿病 64 (Suppl.1) P -3 2021年05月
  • 2型糖尿病患者における血中可溶型T-カドヘリン濃度と臨床パラメータとの関連
    飯岡 雅仁; 福田 士郎; 宮下 かずや; 村井 潤; 中村 正; 堀谷 恵美; 坂上 貴章; 川知 祐介; 沖田 朋憲; 清水 有理; 藤島 裕也; 喜多 俊文; 西澤 均; 前田 法一; 下村 伊一郎 糖尿病 64 (Suppl.1) P -5 2021年05月
  • 藤島 裕也; 木村 優; 徳澤 千恵; 西澤 均; 白波瀬 景子; 川知 祐介; 福田 士郎; 野間 俊樹; 西塔 拓郎; 宮崎 安弘; 前田 和久; 長井 直子; 前田 法一; 土岐 祐一郎; 下村 伊一郎 日本内分泌学会雑誌 97 (1) 275 -275 2021年04月
  • 川知 祐介; 藤島 裕也; 西澤 均; 中村 敬志; 西塔 拓郎; 喜多 俊文; 前田 法一; 下村 伊一郎 日本内分泌学会雑誌 97 (1) 282 -282 2021年04月
  • 畑 雅久; 向井 康祐; 宮下 和幸; 西澤 均; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝昭; 下村 伊一郎 日本内分泌学会雑誌 97 (1) 299 -299 2021年04月
  • 早川 友朗; 川田 哲史; 長江 亮太; 宮下 和幸; 西澤 均; 片上 直人; 小澤 純二; 福原 淳範; 前田 法一; 大井 和哉; 三宅 智博; 島津 研三; 大月 道夫; 下村 伊一郎 日本内分泌学会雑誌 97 (1) 315 -315 2021年04月
  • 藤井 浩平; 大森 一生; 宮下 和幸; 西澤 均; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝昭; 下村 伊一郎 日本内分泌学会雑誌 97 (1) 315 -315 2021年04月
  • 河田 慶太郎; 向井 康祐; 宮下 和幸; 西澤 均; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝昭; 下村 伊一郎 日本内分泌学会雑誌 97 (1) 328 -328 2021年04月
  • 心不全合併によりαブロッカーの増量が困難であり、メチロシンの併用を必要とした褐色細胞腫の1例
    原 智之; 飯田 祐一郎; 向井 康祐; 波多野 浩士; 中本 敬; 宮下 和幸; 福原 慎一郎; 西澤 均; 小澤 純二; 前田 法一; 大月 道夫; 坂田 泰史; 下村 伊一郎 日本内分泌学会雑誌 97 (1) 347 -347 2021年04月
  • 長江 亮太; 木村 武量; 宮下 和幸; 西澤 均; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝昭; 下村 伊一郎 日本内分泌学会雑誌 97 (1) 363 -363 2021年04月
  • 中村勇斗; 喜多俊文; 喜多俊文; 前田法一; 前田法一; 下村伊一郎 日本肥満学会・日本肥満症治療学会合同学術集会プログラム・抄録集 41st-38th (Web) 2021年
  • 仁木 暁子; 奥野 陽亮; 飯岡 雅仁; 早川 友朗; 小澤 純二; 西澤 均; 前田 法一; 三宅 達也; 植村 元秀; 大月 道夫; 下村 伊一郎 日本内分泌学会雑誌 96 (3) 765 -765 2021年01月
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    色摩 茉衣子; 園田 奈央; 森本 明子; 菅 彩香; 田嶋 哲也; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝昭; 下村 伊一郎; 大野 ゆう子 糖尿病 64 (1) 52 -52 2021年01月
  • 短期間にニボルマブで甲状腺機能異常症、下垂体機能低下症、1型糖尿病を発症した1例
    斎藤 匠; 畑 雅久; 向井 康祐; 佐伯 絢; 宮下 和幸; 西澤 均; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝昭; 下村 伊一郎 糖尿病 64 (1) 57 -57 2021年01月
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    早川 友朗; 秦 誠倫; 今田 侑; 宮下 和幸; 西澤 均; 小澤 純二; 福原 淳範; 前田 法一; 大月 道夫; 松岡 孝昭; 下村 伊一郎 糖尿病 64 (1) 63 -63 2021年01月
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    大本 真由; 戸川 有里; 向井 康祐; 早川 友朗; 宮下 和幸; 西澤 均; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝昭; 下村 伊一郎 糖尿病 64 (1) 68 -68 2021年01月
  • 新たな食嗜好質問票の作成とその評価
    徳澤 千恵; 長井 直子; 白波瀬 景子; 木村 優; 福田 士郎; 藤島 裕也; 西澤 均; 前田 法一; 下村 伊一郎 糖尿病 64 (1) 73 -73 2021年01月
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    木村 優; 福田 士郎; 藤島 裕也; 徳澤 千恵; 白波瀬 景子; 長井 直子; 西塔 拓郎; 西澤 均; 前田 法一; 土岐 祐一郎; 下村 伊一郎 糖尿病 64 (1) 73 -73 2021年01月
  • オクトレオチド投与により低血糖が増悪したインスリノーマの1例
    坂本 紗英花; 満塩 研人; 石橋 千咲; 木村 武量; 福井 健司; 西澤 均; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝昭; 下村 伊一郎 糖尿病 64 (1) 85 -85 2021年01月
  • 高度肥満症患者の食行動と外科手術後の体重減少との関連
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  • 【抗糖尿病薬が有する多面的作用とそのメカニズム】抗糖尿病薬の肥満に対する多面的作用とそのメカニズム
    坂上 貴章; 藤島 裕也; 前田 法一 糖尿病・内分泌代謝科 51 (5) 346 -353 2020年11月
  • 佐々木 まゆ奈; 向井 康祐; 河中 聡之; 大瀬 尚子; 仁木 暁子; 宮下 和幸; 西澤 均; 小澤 純二; 前田 法一; 松岡 孝昭; 大月 道夫; 下村 伊一郎 日本内分泌学会雑誌 96 (2) 547 -547 2020年10月
  • 中村 勇斗; 喜多 俊文; 田中 紀實; 福田 士郎; 小幡 佳也; 藤島 裕也; 西澤 均; 前田 法一; 下村 伊一郎 日本内分泌学会雑誌 96 (1) 230 -230 2020年08月
  • 坂上 貴章; 小幡 佳也; 藤島 裕也; 小澤 純二; 西澤 均; 松岡 孝昭; 岩橋 博見; 前田 法一; 大月 道夫; 山本 俊至; 下村 伊一郎 日本内分泌学会雑誌 96 (1) 240 -240 2020年08月
  • 飯岡 雅仁; 早川 友朗; 宮下 和幸; 西澤 均; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝昭; 福原 慎一郎; 下村 伊一郎 日本内分泌学会雑誌 96 (1) 258 -258 2020年08月
  • 細川 吉弥; 小澤 純二; 川知 祐介; 米田 祥; 河盛 段; 西澤 均; 前田 法一; 大月 道夫; 松岡 孝昭; 下村 伊一郎 日本内分泌学会雑誌 96 (1) 277 -277 2020年08月
  • 長江 亮太; 早川 友朗; 宮下 和幸; 西澤 均; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝昭; 下村 伊一郎 日本内分泌学会雑誌 96 (1) 281 -281 2020年08月
  • 沖田 朋憲; 喜多 俊文; 中村 勇斗; 堀谷 恵美; 福田 士郎; 坂上 貴章; 川知 祐介; 清水 有理; 藤島 裕也; 西澤 均; 前田 法一; 下村 伊一郎 日本内分泌学会雑誌 96 (1) 284 -284 2020年08月
  • 栗山 督; 向井 康祐; 早川 友朗; 宮下 和幸; 西澤 均; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝昭; 下村 伊一郎 日本内分泌学会雑誌 96 (1) 320 -320 2020年08月
  • 今田 侑; 藤田 真吾; 宮下 和幸; 西澤 均; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝昭; 下村 伊一郎 日本内分泌学会雑誌 96 (1) 323 -323 2020年08月
  • 秦 誠倫; 藤田 真吾; 向井 康祐; 宮下 和幸; 西澤 均; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝昭; 下村 伊一郎 日本内分泌学会雑誌 96 (1) 336 -336 2020年08月
  • 早川 友朗; 大本 真由; 秦 誠倫; 宮下 和幸; 西澤 均; 小澤 純二; 福原 淳範; 前田 法一; 大月 道夫; 松岡 孝昭; 下村 伊一郎 日本内分泌学会雑誌 96 (1) 337 -337 2020年08月
  • 福田 士郎; 喜多 俊文; 宮下 かずや; 中村 勇斗; 清水 有理; 沖田 朋憲; 川知 祐介; 増田 重樹; 田中 紀實; 小幡 佳也; 藤島 裕也; 西澤 均; 前田 法一; 下村 伊一郎 日本内分泌学会雑誌 96 (1) 341 -341 2020年08月
  • 竹本 有里; 早川 友朗; 三浦 慎平; 中川 智義; 向井 康祐; 宮下 和幸; 西澤 均; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝昭; 押野 悟; 齋藤 洋一; 下村 伊一郎 日本内分泌学会雑誌 96 (1) 344 -344 2020年08月
  • 川田 哲史; 向井 康祐; 石橋 千咲; 宮下 和幸; 西澤 均; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝昭; 下村 伊一郎 日本内分泌学会雑誌 96 (1) 362 -362 2020年08月
  • 稲田 慎也; 木村 武量; 中田 継一; 植田 康敬; 宮下 和幸; 西澤 均; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝昭; 下村 伊一郎 日本内分泌学会雑誌 96 (1) 372 -372 2020年08月
  • 高度肥満症に対して腹腔鏡下スリーブ状胃切除術を施行した一例 食行動に着目した分析
    木村 優; 早川 友朗; 西澤 均; 藤島 裕也; 福田 士郎; 白波瀬 景子; 徳澤 千恵; 長井 直子; 西塔 拓郎; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝昭; 土岐 祐一郎; 下村 伊一郎 糖尿病 63 (Suppl.1) S -161 2020年08月
  • ニボルマブ投与後に糖尿病発症と膵外分泌酵素上昇を呈した透析患者の一例
    籠田 芳夫; 木村 武量; 細川 吉弥; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝昭; 下村 伊一郎 糖尿病 63 (Suppl.1) S -316 2020年08月
  • 抗PD-1抗体投与により膵外分泌障害を生じるも内因性インスリン分泌能は維持された1例
    木村 武量; 西澤 均; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝昭; 下村 伊一郎 糖尿病 63 (Suppl.1) S -316 2020年08月
  • 2型糖尿病・高度肥満症における血漿XORの変化
    川知 祐介; 藤島 裕也; 村瀬 貴代; 中村 敬志; 宮崎 安弘; 西澤 均; 喜多 俊文; 前田 法一; 土岐 祐一郎; 下村 伊一郎 メタボリックシンドローム 16 (1) 22 -24 2020年07月
  • 急性膵炎を繰り返した若年高中性脂肪血症例とその母親に対する全エクソーム解析
    藤田 真吾; 西澤 均; 今田 侑; 山口 崇; 村野 武義; 武城 英明; 石橋 千咲; 木村 武量; 宮下 和幸; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝明; 下村 伊一郎 日本動脈硬化学会総会プログラム・抄録集 52回 225 -225 2020年07月
  • 小幡 佳也; 中野 依莉子; 小澤 純二; 西澤 均; 前田 法一; 大月 道夫; 松岡 孝昭; 高野 徹; 岩橋 博見; 下村 伊一郎 日本内分泌学会雑誌 95 (4) 1357 -1357 2020年02月
  • 向井 康祐; 小幡 佳也; 吉田 朋世; 高山 理沙; 福原 慎一郎; 木内 寛; 山崎 有人; 西澤 均; 前田 法一; 野々村 夫; 笹野 公伸; 大月 道夫; 下村 伊一郎 日本内分泌学会雑誌 95 (4) 1692 -1692 2020年02月
  • 川知 祐介; 藤島 裕也; 西澤 均; 前田 法一; 下村 伊一郎 循環器内科 87 (1) 20 -27 2020年01月
  • 坂上 貴章; 奥野 陽亮; 向井 康祐; 藤田 真吾; 小澤 純二; 西澤 均; 松岡 孝昭; 岩橋 博見; 前田 法一; 山崎 有人; 笹野 公伸; 大月 道夫; 下村 伊一郎 日本内分泌学会雑誌 95 (3) 1136 -1136 2020年01月
  • 中村 勇斗; 喜多 俊文; 小幡 佳也; 福田 士郎; 田中 紀實; 藤島 裕也; 西澤 均; 前田 法一; 下村 伊一郎 肥満研究 25 (Suppl.) 244 -244 2019年10月
  • 糖尿病・メタボリックシンドロームと心血管疾患病態治療学の最前線 アディポネクチン/T-カドヘリンを介した心血管疾患病態治療学
    下村 伊一郎; 中村 勇斗; 喜多 俊文; 福田 士郎; 小幡 佳也; 藤島 裕也; 前田 法一 日本動脈硬化学会総会プログラム・抄録集 51回 S17 -2 2019年07月
  • 脂肪細胞由来血管保護因子、アディポネクチンの解析 新概念の内分泌因子としての性質
    船橋 徹; 藤島 裕也; 福田 士郎; 長尾 博文; 増田 重樹; 小幡 佳也; 田中 紀實; 中村 勇斗; 松田 圭介; 堰本 亮平; 森 卓也; 山岡 正弥; 西澤 均; 喜多 俊文; 前田 法一; 下村 伊一郎 メタボリックシンドローム 15 (1) 9 -18 2019年07月
  • 先端巨大症における下垂体機能低下症の合併率及び腫瘍径との関係
    大畔 健太; 向井 康祐; 小澤 純二; 西澤 均; 前田 法一; 大月 道夫; 松岡 孝昭; 岩橋 博見; 押野 悟; 齋藤 洋一; 下村 伊一郎 日本内分泌学会雑誌 95 (1) 384 -384 2019年04月
  • 心不全急性期にIGF-1低値であり、心不全軽快後にIGF-1値の経時的上昇を認めた下垂体性巨人症の一例
    柏木 理佐; 木村 武量; 向井 康祐; 小澤 純二; 西澤 均; 前田 法一; 大月 道夫; 松岡 孝昭; 岩橋 博見; 齋藤 洋一; 下村 伊一郎 日本内分泌学会雑誌 95 (1) 415 -415 2019年04月
  • 大畔 健太; 向井 康祐; 小澤 純二; 西澤 均; 前田 法一; 大月 道夫; 松岡 孝昭; 岩橋 博見; 押野 悟; 齋藤 洋一; 下村 伊一郎 日本内分泌学会雑誌 95 (1) 384 -384 2019年04月
  • 藤島 裕也; 川知 祐介; 長尾 博文; 西澤 均; 中山 康宗; 馬場 健史; 永森 収志; 金井 好克; 喜多 俊文; 前田 法一; 福崎 英一郎; 下村 伊一郎 日本内分泌学会雑誌 95 (1) 398 -398 2019年04月
  • 柏木 理佐; 木村 武量; 向井 康祐; 小澤 純二; 西澤 均; 前田 法一; 大月 道夫; 松岡 孝昭; 岩橋 博見; 齋藤 洋一; 下村 伊一郎 日本内分泌学会雑誌 95 (1) 415 -415 2019年04月
  • 中野 依莉子; 小幡 佳也; 小澤 純二; 西澤 均; 前田 法一; 大月 道夫; 松岡 孝昭; 高野 徹; 岩橋 博見; 下村 伊一郎 日本内分泌学会雑誌 95 (1) 418 -418 2019年04月
  • 川知 祐介; 藤島 裕也; 村瀬 貴代; 中村 敬志; 宮崎 安弘; 西澤 均; 喜多 俊文; 前田 法一; 土岐 祐一郎; 下村 伊一郎 日本内分泌学会雑誌 95 (1) 437 -437 2019年04月
  • 細江 重郎; 向井 康祐; 小澤 純二; 西澤 均; 前田 法一; 大月 道夫; 松岡 孝昭; 岩橋 博見; 下村 伊一郎 日本内分泌学会雑誌 95 (1) 438 -438 2019年04月
  • 常田 和宏; 藤田 真吾; 小澤 純二; 西澤 均; 前田 法一; 大月 道夫; 松岡 孝昭; 岩橋 博見; 田中 知明; 下村 伊一郎 日本内分泌学会雑誌 95 (1) 441 -441 2019年04月
  • 堀井 知美; 奥野 陽亮; 小澤 純二; 西澤 均; 前田 法一; 大月 道夫; 松岡 孝昭; 岩橋 博見; 下村 伊一郎 日本内分泌学会雑誌 95 (1) 441 -441 2019年04月
  • 高森 朋世; 向井 康祐; 小澤 純二; 西澤 均; 中田 幸子; 前田 法一; 大月 道夫; 松岡 孝昭; 岩橋 博美; 下村 伊一郎 日本内分泌学会雑誌 95 (1) 465 -465 2019年04月
  • 臓器間クロストークによる糖代謝制御:神経因子と液性因子の役割 恒常性の維持 Adiponectin、T-cadherin、exosomeによる器官のクロストーク(Keeping homeostasis: organ cross-talks by adiponectin, T-cadherin, and exosomes)
    喜多 俊文; 福田 士郎; 沖田 朋憲; 前田 法一; 下村 伊一郎 糖尿病 62 (Suppl.1) S -22 2019年04月
  • 慢性炎症と糖尿病:血糖調節の破綻と合併症におけるその意義 アディポネクチンによるエキソソーム分泌は圧過負荷心不全モデルにおけるMSC移植による心機能の改善に寄与する(Exosome Secretion by Adiponectin Contributes to MSC Transplantation in Pressure Overload Heart Failure Models)
    喜多 俊文; 中村 勇斗; 前田 法一; 下村 伊一郎 糖尿病 62 (Suppl.1) S -42 2019年04月
  • アディポネクチンの組織集積のメカニズムと,その抗糖尿病作用および臓器保護作用の解明
    藤島 裕也; 小幡 佳也; 福田 士郎; 喜多 俊文; 西澤 均; 前田 法一; 下村 伊一郎 糖尿病 62 (Suppl.1) S -101 2019年04月
  • 膵腎同時移植後5年目にグラフト十二指腸穿孔を発症した1例
    坂上 貴章; 宮下 和幸; 浅岡 忠史; 岩上 佳史; 渡邉 裕尭; 小幡 佳也; 西澤 均; 前田 法一; 松岡 孝昭; 後藤 邦仁; 江口 英利; 伊藤 壽記; 下村 伊一郎 糖尿病 62 (Suppl.1) S -169 2019年04月
  • 家族性部分性脂肪萎縮症が疑われた糖尿病の一例
    小幡 佳也; 佐々木 まゆ奈; 小澤 純二; 西澤 均; 前田 法一; 大月 道夫; 松岡 孝昭; 岩橋 博見; 海老原 健; 下村 伊一郎 糖尿病 62 (Suppl.1) S -175 2019年04月
  • 腎臓におけるAdiponectin・T-cadherinの局在と機能解析
    清水 有理; 藤島 裕也; 沖田 朋憲; 川知 祐介; 中村 勇斗; 田中 紀實; 増田 重樹; 小幡 佳也; 福田 士郎; 喜多 俊文; 西澤 均; 前田 法一; 下村 伊一郎 糖尿病 62 (Suppl.1) S -179 2019年04月
  • 慢性心不全モデルにおけるアディポネクチン/T-カドヘリンシステム
    中村 勇斗; 喜多 俊文; 福田 士郎; 小幡 佳也; 田中 紀實; 増田 重樹; 清水 有理; 沖田 朋憲; 川知 祐介; 西澤 均; 前田 法一; 下村 伊一郎 糖尿病 62 (Suppl.1) S -185 2019年04月
  • アディポネクチン/TカドヘリンシステムとERストレスに関する検討
    沖田 朋憲; 喜多 俊文; 中村 勇斗; 嶺尾 良平; 福田 士郎; 小幡 佳也; 川知 祐介; 田中 紀實; 増田 重樹; 清水 有理; 西澤 均; 前田 法一; 下村 伊一郎 糖尿病 62 (Suppl.1) S -186 2019年04月
  • 肥満・糖尿病病態における血中ならびに組織T-カドヘリンの関連
    福田 士郎; 喜多 俊文; 宮下 かずや; 中村 勇斗; 川知 祐介; 沖田 朋憲; 清水 有里; 田中 紀實; 増田 重樹; 小幡 佳也; 藤島 裕也; 西澤 均; 前田 法一; 下村 伊一郎 糖尿病 62 (Suppl.1) S -186 2019年04月
  • 重症心不全治療時,カテコラミン投与下で強いインスリン抵抗性を示した2症例
    木村 武量; 小澤 純二; 西澤 均; 前田 法一; 大月 道夫; 松岡 孝昭; 岩橋 博見; 下村 伊一郎 糖尿病 62 (Suppl.1) S -251 2019年04月
  • アディポネクチンのT-カドヘリンを介する骨格筋再生促進作用
    田中 紀實; 喜多 俊文; 西澤 均; 福田 士郎; 藤島 裕也; 小幡 佳也; 長尾 博文; 増田 重樹; 中村 勇斗; 清水 有里; 嶺尾 良平; ランシュット・バ-バラ; 深田 宗一郎; 前田 法一; 下村 伊一郎 糖尿病 62 (Suppl.1) S -275 2019年04月
  • 日本人2型糖尿病患者において空腹時グルカゴン値は血中Cペプチド値と正相関する
    細川 吉弥; 小澤 純二; 西澤 均; 河盛 段; 前田 法一; 大月 道夫; 松岡 孝昭; 岩橋 博見; 下村 伊一郎 糖尿病 62 (Suppl.1) S -278 2019年04月
  • 早朝空腹時には低血糖を認めなかったインスリノーマ症例の組織学的検討
    豊田 新一郎; 米田 祥; 向井 康祐; 奥野 陽亮; 小澤 純二; 西澤 均; 前田 法一; 大月 道夫; 松岡 孝昭; 岩橋 博見; 下村 伊一郎 糖尿病 62 (Suppl.1) S -353 2019年04月
  • 川知 祐介; 藤島 裕也; 村瀬 貴代; 中村 敬志; 宮崎 安弘; 西澤 均; 喜多 俊文; 前田 法一; 土岐 祐一郎; 下村 伊一郎 メタボリックシンドローム = Journal of metabolic syndrome 16 (1) 22 -24 2019年
  • 奥野 陽亮; 山本 研人; 向井 康祐; 小澤 純二; 西澤 均; 前田 法一; 松岡 孝昭; 岩橋 博見; 押野 悟; 大月 道夫; 斎藤 洋一; 下村 伊一郎 日本内分泌学会雑誌 94 (3) 997 -997 2018年12月
  • 大月 道夫; 奥野 陽亮; 山本 研人; 向井 康祐; 小澤 純二; 西澤 均; 前田 法一; 松岡 孝昭; 岩橋 博見; 押野 悟; 齋藤 洋一; 下村 伊一郎 日本内分泌学会雑誌 94 (4) 1694 -1694 2018年12月
  • 伊藤 直彦; 向井 康祐; 米田 祥; 奥野 陽亮; 小澤 純二; 西澤 均; 前田 法一; 大月 道夫; 松岡 孝昭; 岩崎 博見; 下村 伊一郎 日本内分泌学会雑誌 94 (2) 689 -689 2018年09月
  • 福田 士郎; 喜多 俊文; 小幡 佳也; 藤島 裕也; 長尾 博文; 増田 重樹; 田中 紀實; 西澤 均; 船橋 徹; 前田 法一; 下村 伊一郎 肥満研究 24 (Suppl.) 203 -203 2018年09月
  • 川知 祐介; 長尾 博文; 藤島 裕也; 西澤 均; 中山 康宗; 馬場 健史; 永森 收志; 金井 好克; 喜多 俊文; 福田 士郎; 前田 法一; 福崎 英一郎; 下村 伊一郎 肥満研究 24 (Suppl.) 224 -224 2018年09月
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    田中 紀實; 喜多 俊文; 深田 宗一朗; 西澤 均; 清水 有理; 嶺尾 良平; 増田 重樹; 小幡 佳也; 長尾 博文; 福田 士郎; 藤島 裕也; 前田 法一; 下村 伊一郎 日本筋学会学術集会プログラム・抄録集 3回 120 -120 2017年07月
  • 急性心筋梗塞における血中アディポネクチン値と梗塞サイズ
    前田 法一; 夏川 知輝; 福田 士郎; 山岡 正弥; 藤島 裕也; 長尾 博文; 佐藤 芙美; 西澤 均; 澤野 宏隆; 林 靖之; 甲斐 達朗; 船橋 徹; 下村 伊一郎 日本動脈硬化学会総会プログラム・抄録集 49回 256 -256 2017年06月
  • 重症病態では単球のアディポネクチン運搬能は、単球の分化誘導と関連して減少する
    梅村 穣; 清水 健太郎; 小倉 裕司; 康 泰珍; 夏川 知輝; 前田 法一; 船橋 徹; 下村 伊一郎; 嶋津 岳士 日本外傷学会雑誌 31 (2) 268 -268 2017年05月
  • 小幡 佳也; 喜多 俊文; 藤島 裕也; 福田 士郎; 長尾 博文; 増田 重樹; 田中 紀實; 西澤 均; 前田 法一; 下村 伊一郎 日本内分泌学会雑誌 93 (1) 247 -247 2017年04月
  • 佐伯 絢; 向井 康祐; 仁科 周平; 林 令子; 村田 雅彦; 玉田 大介; 北村 哲宏; 前田 法一; 松岡 孝昭; 今川 彰久; 大月 道夫; 下村 伊一郎 日本内分泌学会雑誌 93 (1) 300 -300 2017年04月
  • 嶺尾 良平; 向井 康祐; 大月 道夫; 木村 武量; 小澤 純二; 前田 法一; 松岡 孝昭; 今川 彰久; 下村 伊一郎 日本内分泌学会雑誌 93 (1) 315 -315 2017年04月
  • 仁科 周平; 向井 康祐; 嶺尾 良平; 小澤 純二; 前田 法一; 松岡 孝昭; 今川 彰久; 大月 道夫; 下村 伊一郎; 島田 菜津子; 後藤 範子; 清原 英司; 片山 一朗 日本内分泌学会雑誌 93 (1) 321 -321 2017年04月
  • 小澤 栄稔; 坂本 扶美枝; 久保 典代; 宮下 和幸; 山岡 正弥; 小澤 純二; 中田 幸子; 前田 法一; 大月 道夫; 松岡 孝昭; 高野 徹; 今川 彰久; 下村 伊一郎 日本内分泌学会雑誌 93 (1) 323 -323 2017年04月
  • 周 邦彦; 久保 典代; 宮下 和幸; 山岡 正弥; 坂本 扶美枝; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝昭; 今川 彰久; 下村 伊一郎 日本内分泌学会雑誌 93 (1) 339 -339 2017年04月
  • 増田 重樹; 藤島 裕也; 福田 士郎; 田中 紀實; 小幡 佳也; 長尾 博文; 山岡 正弥; 喜多 俊文; 西澤 均; 前田 法一; 船橋 徹; 下村 伊一郎 日本内分泌学会雑誌 93 (1) 368 -368 2017年04月
  • アディポネクチン/T-カドヘリンシステムは、エクソソーム合成促進を介して細胞内セラミド含量を低下させる
    小幡 佳也; 喜多 俊文; 藤島 裕也; 福田 士郎; 長尾 博文; 増田 重樹; 田中 紀實; 西澤 均; 前田 法一; 下村 伊一郎 糖尿病 60 (Suppl.1) S -137 2017年04月
  • 選択的動脈内カルシウム注入静脈サンプリング法においてインスリン分泌が遅延増加反応を示した多発インスリノーマの1例
    早川 友朗; 木村 武量; 小澤 純二; 北村 哲宏; 前田 法一; 福原 淳範; 松岡 孝昭; 今川 彰久; 大月 道夫; 下村 伊一郎 糖尿病 60 (Suppl.1) S -209 2017年04月
  • 2型糖尿病患者における腹部肥満およびサルコペニアの実態調査
    村井 潤; 大塚 章人; 西澤 均; 酒井 保奈; 鈴木 正英; 横田 真二; 完山 昌隆; 市原 紀久雄; 前田 法一; 中村 正; 下村 伊一郎 糖尿病 60 (Suppl.1) S -240 2017年04月
  • 骨格筋に着目した腹部肥満2型糖尿病患者の臨床像
    西澤 均; 村井 潤; 大塚 章人; 酒井 保奈; 鈴木 正英; 横田 真二; 福田 士郎; 市原 紀久男; 前田 法一; 中村 正; 下村 伊一郎 糖尿病 60 (Suppl.1) S -240 2017年04月
  • GPIアンカー切断酵素GPI-PLDが、糖・脂質代謝に与える影響
    藤島 裕也; 増田 重樹; 喜多 俊文; 西澤 均; 前田 法一; 下村 伊一郎 糖尿病 60 (Suppl.1) S -283 2017年04月
  • ヒト脂肪組織におけるプリン異化代謝産物の分泌
    長尾 博文; 西澤 均; 深田 唯史; 水島 恒和; 田中 紀實; 對馬 佑; 喜多 俊文; 前田 法一; 森 正樹; 下村 伊一郎 糖尿病 60 (Suppl.1) S -358 2017年04月
  • アディポネクチンがT-カドヘリンに結合する部位と、その増加作用に関する考察
    福田 士郎; 喜多 俊文; 増田 重樹; 小幡 佳也; 田中 紀實; 長尾 博文; 藤島 裕也; 西澤 均; 船橋 徹; 前田 法一; 下村 伊一郎 糖尿病 60 (Suppl.1) S -359 2017年04月
  • アディポネクチン結合蛋白T-カドヘリンのメタロプロテアーゼADAM12による切断制御
    喜多 俊文; 小幡 佳也; 藤島 裕也; 長尾 博文; 増田 重樹; 田中 紀寛; 西澤 均; 船橋 徹; 前田 法一; 下村 伊一郎 糖尿病 60 (Suppl.1) S -359 2017年04月
  • テストステロン欠乏下での骨格筋T-カドヘリンの遺伝子発現、アディポネクチン集積の制御に関する検討
    田中 紀實; 喜多 俊文; 西澤 均; 福田 士郎; 長尾 博文; 小幡 佳也; 増田 重樹; 藤島 裕也; 前田 法一; 下村 伊一郎 糖尿病 60 (Suppl.1) S -470 2017年04月
  • 小澤 純二; 藤田 真吾; 大森 一生; 木村 武量; 前田 法一; 大月 道夫; 松岡 孝昭; 岩橋 博見; 今川 彰久; 下村 伊一郎 日本内分泌学会雑誌 93 (1) 306 -306 2017年04月
  • 永井 泰紀; 向井 康祐; 木村 武量; 山岡 正弥; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝昭; 岩橋 博見; 今川 彰久; 下村 伊一郎 日本内分泌学会雑誌 93 (1) 349 -349 2017年04月
  • 清水 有理; 木村 武量; 永井 泰紀; 向井 康祐; 山岡 正弥; 小澤 純二; 宮村 能子; 石津谷 祐; 木内 寛; 武鑓 美沙; 和田 直樹; 前田 法一; 大月 道夫; 松岡 孝昭; 岩橋 博見; 今川 彰久; 下村 伊一郎 日本内分泌学会雑誌 93 (1) 381 -381 2017年04月
  • 再発性多発軟骨炎にIL-6阻害薬トシリズマブを投与中1型糖尿病を発症した1例
    木村 武量; 西谷 重紀; 高原 充佳; 坂本 扶美枝; 小澤 純二; 前田 法一; 大月 道夫; 松岡 孝昭; 岩橋 博見; 今川 彰久; 下村 伊一郎 糖尿病 60 (Suppl.1) S -232 2017年04月
  • 急激な血糖改善後に下肢筋力低下と橋中心髄鞘崩壊症(CPM)様の画像所見を来した1型糖尿病症例
    清水 有理; 木村 武量; 小澤 純二; 矢田 知大; 村瀬 翔; 望月 秀樹; 前田 法一; 大月 道夫; 松岡 孝昭; 岩橋 博見; 今川 彰久; 下村 伊一郎 糖尿病 60 (Suppl.1) S -346 2017年04月
  • 長尾 博文; 西澤 均; 深田 唯史; 水島 恒和; 田中 紀實; 對馬 佑; 藤島 裕也; 喜多 俊文; 船橋 徹; 前田 法一; 森 正樹; 下村 伊一郎 メタボリックシンドローム = Journal of metabolic syndrome 14 (1) 15 -17 2017年
  • 仁科 周平; 和田 万葉; 向井 康祐; 小澤 純二; 呉村 有紀; 押野 悟; 齋藤 洋一; 前田 法一; 松岡 孝昭; 今川 彰久; 大月 道夫; 下村 伊一郎 日本内分泌学会雑誌 92 (S.Branc) 223 -223 2016年12月
  • 前田 法一; 下村 伊一郎 糖尿病 59 (11) 726 -729 2016年11月
  • Norikazu Maeda; Iichiro Shimomura DIABETES RESEARCH AND CLINICAL PRACTICE 120 S26 -S26 2016年10月
  • 長尾博文; 西澤均; 馬場健史; 中山泰宗; 永森收志; 金井好克; 喜多俊文; 喜多俊文; 田中紀實; 福田士郎; 前田法一; 前田法一; 船橋徹; 船橋徹; 福崎英一郎; 下村伊一郎 肥満研究 22 (Supplement) 227 2016年09月
  • 西澤均; 長尾博文; 深田唯史; 水島恒和; 田中紀實; 對馬佑; 田村みずほ; 喜多俊文; 山岡正弥; 船橋徹; 森正樹; 前田法一; 下村伊一郎 肥満研究 22 (Supplement) 243 2016年09月
  • 前田 法一; 堰本 亮平; 福田 士郎; 船橋 徹; 石井 優; 下村 伊一郎 肥満研究 22 (Suppl.) 154 -154 2016年09月
  • 喜多 俊文; 小幡 佳也; 藤島 裕也; 福田 士郎; 長尾 博文; 増田 重樹; 田中 紀實; 山岡 正弥; 西澤 均; 船橋 徹; 前田 法一; 下村 伊一郎 肥満研究 22 (Suppl.) 180 -180 2016年09月
  • 増田 重樹; 藤島 裕也; 松田 圭介; 福田 士郎; 小幡 佳也; 長尾 博文; 田中 紀實; 山岡 正弥; 喜多 俊文; 西澤 均; 前田 法一; 船橋 徹; 下村 伊一郎 肥満研究 22 (Suppl.) 228 -228 2016年09月
  • 藤島 裕也; 増田 重樹; 山岡 正弥; 喜多 俊文; 西澤 均; 前田 法一; 船橋 徹; 下村 伊一郎 肥満研究 22 (Suppl.) 228 -228 2016年09月
  • 前田 法一; 夏川 知輝; 福田 士郎; 山岡 正弥; 藤島 裕也; 長尾 博文; 佐藤 芙美; 西澤 均; 澤野 宏隆; 林 靖之; 甲斐 達朗; 船橋 徹; 下村 伊一郎 肥満研究 22 (Suppl.) 244 -244 2016年09月
  • 藤島 裕也; 前田 法一 尿酸と血糖 2 (3) 134 -137 2016年07月
  • 前田 法一; 堰本 亮平; 福田 士郎; 對馬 佑; 松田 圭介; 森 卓也; 中辻 秀朗; 西澤 均; 岸田 堅; 菊田 順一; 舞島 弓子; 船橋 徹; 石井 優; 下村 伊一郎 日本内分泌学会雑誌 92 (1) 214 -214 2016年04月
  • 増田 重樹; 藤島 裕也; 松田 圭介; 福田 士郎; 田中 紀實; 小幡 佳也; 長尾 博文; 山岡 正弥; 喜多 俊文; 西澤 均; 前田 法一; 船橋 徹; 下村 伊一郎 日本内分泌学会雑誌 92 (1) 215 -215 2016年04月
  • 肥満糖尿病の病態解明と治療法の開発 病態と臓器障害・合併症の観点から 肥満および糖尿病の心血管系におけるアディポネクチン/T-カドヘリンの保護的役割(New mechanisms and treatments for obese type 2 diabetes: from the aspects of pathophysiology, organ damages, and complications Protective role of adiponectin/T-cadherin system on cardiovasculature in obesity and diabetes)
    前田 法一; 下村 伊一郎 糖尿病 59 (Suppl.1) S -99 2016年04月
  • 肥満脂肪組織におけるin vivoメタボロミクス動態解析 グルタミン酸上昇とその病態学的意義
    長尾 博文; 西澤 均; 馬場 健史; 中山 泰宗; 永森 收志; 金井 好克; 喜多 俊文; 田中 紀實; 福田 士郎; 前田 法一; 船橋 徹; 福崎 英一郎; 下村 伊一郎 糖尿病 59 (Suppl.1) S -139 2016年04月
  • 2型糖尿病におけるサルコペニア合併の意義の検討
    高井 研次; 山岡 正弥; 前田 法一; 西澤 均; 船橋 徹; 下村 伊一郎 糖尿病 59 (Suppl.1) S -190 2016年04月
  • 当院入院患者におけるリラグルチド、リキシセナチド及びインスリンの短期投与が食行動に与える影響についての検討
    田中 紀實; 山岡 正弥; 増田 重樹; 小幡 佳也; 長尾 博文; 福田 士郎; 藤島 裕也; 喜多 俊文; 西澤 均; 前田 法一; 船橋 徹; 下村 伊一郎 糖尿病 59 (Suppl.1) S -207 2016年04月
  • 内臓脂肪・皮下脂肪蓄積が末梢血遺伝子発現に及ぼす影響
    小幡 佳也; 前田 法一; 山田 祐也; 山本 浩司; 山岡 正弥; 田中 紀實; 増田 重樹; 長尾 博文; 福田 士郎; 藤島 裕也; 喜多 俊文; 西澤 均; 船橋 徹; 松澤 佑次; 下村 伊一郎 糖尿病 59 (Suppl.1) S -335 2016年04月
  • 生活習慣の欧米化はアディポネクチンの量だけでなく質にも影響する
    久保田 麻衣子; 米田 真康; 久保田 益亘; 大久保 博史; 前田 修作; 大野 晴也; 沖 健司; 前田 法一; 船橋 徹; 下村 伊一郎 糖尿病 59 (Suppl.1) S -336 2016年04月
  • 当院におけるSGLT2阻害薬効果例の投与前予測因子に関する検討
    山岡 正弥; 前田 法一; 西澤 均; 船橋 徹; 下村 伊一郎 糖尿病 59 (Suppl.1) S -384 2016年04月
  • T-cadherinを介したアディポネクチンの組織集積と血管保護作用
    藤島 裕也; 松田 圭介; 森 卓也; 山岡 正弥; 喜多 俊文; 西澤 均; 前田 法一; 船橋 徹; 下村 伊一郎 糖尿病 59 (Suppl.1) S -453 2016年04月
  • 長尾博文; 西澤均; 馬場健史; 中山泰宗; 永森收志; 金井好克; 喜多俊文; 喜多俊文; 田中紀實; 前田法一; 船橋徹; 船橋徹; 福崎英一郎; 下村伊一郎 日本内分泌学会雑誌 92 (1) 201 2016年04月
  • 西澤均; 長尾博文; 深田唯史; 水島恒和; 田中紀實; 對馬佑; 田村みずほ; 喜多俊文; 山岡正弥; 前田法一; 森正樹; 船橋徹; 下村伊一郎 日本内分泌学会雑誌 92 (1) 312 2016年04月
  • ヒト末梢血遺伝子発現プロファイル解析を通じた新規生活習慣病関連遺伝子の発現制御解析と機能解明
    前田 法一 医科学応用研究財団研究報告 33 330 -340 2016年02月
  • 小幡 佳也; 前田 法一; 山田 祐也; 山本 浩司; 山岡 正弥; 田中 紀實; 増田 重樹; 長尾 博文; 福田 士郎; 藤島 裕也; 喜多 俊文; 西澤 均; 船橋 徹; 松澤 佑次; 下村 伊一郎 メタボリックシンドローム = Journal of metabolic syndrome 13 (1) 4 -6 2016年
  • 長尾博文; 西澤均; 馬場健史; 中山泰宗; 永森收志; 金井好克; 喜多俊文; 田中紀實; 福田士郎; 前田法一; 船橋徹; 福崎英一郎; 下村伊一郎 肥満研究 21 (Supplement) 153 2015年09月
  • 前田 法一; 堰本 亮平; 福田 士郎; 對馬 佑; 松田 圭介; 森 卓也; 中辻 秀朗; 西澤 均; 岸田 堅; 菊田 順一; 舞島 弓子; 船橋 徹; 石井 優; 下村 伊一郎 肥満研究 21 (Suppl.) 175 -175 2015年09月
  • 福田 士郎; 平田 歩; 西澤 均; 長尾 博文; 木村 武量; 藤島 裕也; 井上 佳菜; 増田 重樹; 山岡 正弥; 樫根 晋; 小澤 純二; 岸田 堅; 前田 法一; 今川 彰久; 船橋 徹; 下村 伊一郎 肥満研究 21 (Suppl.) 182 -182 2015年09月
  • 肥満における時計遺伝子Period homolog 1(Per1)の発現制御と脂肪組織低体温
    山岡 正弥; 前田 法一; 堰本 亮平; 對馬 佑; 松田 圭介; 森 卓也; 井上 佳菜; 西澤 均; 船橋 徹; 下村 伊一郎 日本動脈硬化学会総会プログラム・抄録集 47回 210 -210 2015年06月
  • インクレチン関連薬であるGLP-1受容体作動薬が体重・食行動・脂質に及ぼす影響
    前田 法一; 井上 佳菜; 藤島 裕也; 福田 士郎; 樫根 晋; 平田 歩; 山岡 正弥; 西澤 均; 船橋 徹; 下村 伊一郎 日本動脈硬化学会総会プログラム・抄録集 47回 262 -262 2015年06月
  • 福田 士郎; 平田 歩; 西澤 均; 長尾 博文; 木村 武量; 藤島 裕也; 樫根 晋; 小澤 純二; 北村 哲宏; 安田 哲行; 前田 法一; 今川 彰久; 船橋 徹; 下村 伊一郎 メタボリックシンドローム 11 (1) 36 -38 2015年06月
  • 長尾博文; 西澤均; 中山泰宗; 馬場健史; 福崎英一郎; 喜多俊文; 増田重樹; 小幡佳也; 福田士郎; 藤島裕也; 山岡正弥; 前田法一; 船橋徹; 下村伊一郎 糖尿病 58 (Supplement 1) S.258 2015年04月
  • 藤島 裕也; 森 卓也; 松田 圭介; 喜多 俊文; 西澤 均; 前田 法一; 船橋 徹; 下村 伊一郎 日本内分泌学会雑誌 91 (1) 260 -260 2015年04月
  • 前田 法一; 森 卓也; 小山 佳之; 中村 雪子; 藤島 裕也; 松田 圭介; 船橋 徹; 島田 昌一; 下村 伊一郎 日本内分泌学会雑誌 91 (1) 334 -334 2015年04月
  • 西澤 均; 福田 士郎; 平田 歩; 長尾 博文; 樫根 晋; 木村 武量; 井上 佳菜; 藤島 裕也; 山岡 正弥; 小澤 純二; 北村 哲宏; 安田 哲行; 前田 法一; 今川 彰久; 船橋 徹; 下村 伊一郎 日本内分泌学会雑誌 91 (1) 392 -392 2015年04月
  • 福田 士郎; 平田 歩; 西澤 均; 長尾 博文; 木村 武量; 藤島 裕也; 井上 佳菜; 増田 重樹; 山岡 正弥; 樫根 晋; 小澤 純二; 岸田 堅; 前田 法一; 今川 彰久; 船橋 徹; 下村 伊一郎 日本内分泌学会雑誌 91 (1) 393 -393 2015年04月
  • 肥満の病態と治療戦略の最前線 現代人はなぜ太る? メタボリックシンドロームにおけるアディポネクチンとS100A8の意義
    前田 法一; 船橋 徹; 下村 伊一郎 糖尿病 58 (Suppl.1) S -45 2015年04月
  • ミトコンドリア遺伝子変異を認めた若年発症糖尿病の1例
    出口 有近; 山岡 正弥; 木村 武量; 小澤 純二; 北村 哲宏; 安田 哲行; 西澤 均; 前田 法一; 松岡 孝昭; 大月 道夫; 今川 彰久; 船橋 徹; 下村 伊一郎 糖尿病 58 (Suppl.1) S -227 2015年04月
  • 2型糖尿病患者でのリキシセナチド投与が食行動に与える影響について
    田中 紀實; 山岡 正弥; 小澤 純二; 北村 哲宏; 安田 哲行; 西澤 均; 前田 法一; 松岡 孝昭; 大月 道夫; 今川 彰久; 船橋 徹; 下村 伊一郎 糖尿病 58 (Suppl.1) S -419 2015年04月
  • アディポネクチン結合タンパクT-カドヘリンの代謝調節
    喜多 俊文; 小幡 佳也; 増田 重樹; 長尾 博文; 福田 士郎; 藤島 裕也; 山岡 正弥; 西澤 均; 前田 法一; 船橋 徹; 下村 伊一郎 糖尿病 58 (Suppl.1) S -425 2015年04月
  • 血中エクソソームとアディポネクチン
    小幡 佳也; 喜多 俊文; 増田 重樹; 長尾 博文; 福田 士郎; 藤島 裕也; 山岡 正弥; 西澤 均; 前田 法一; 船橋 徹; 下村 伊一郎 糖尿病 58 (Suppl.1) S -425 2015年04月
  • GPIアンカー切断酵素とAdipo及びTcadの発現調節連関
    増田 重樹; 藤島 裕也; 松田 圭介; 福田 士郎; 小幡 佳也; 長尾 博文; 山岡 正弥; 喜多 俊文; 西澤 均; 前田 法一; 船橋 徹; 下村 伊一郎 糖尿病 58 (Suppl.1) S -425 2015年04月
  • 肥満脂肪細胞における時計遺伝子Period homolog 1(Per 1)の発現制御と肥満脂肪組織低体温
    山岡 正弥; 前田 法一; 堰本 亮平; 對馬 佑; 松田 圭介; 森 卓也; 井上 佳菜; 西澤 均; 船橋 徹; 下村 伊一郎 糖尿病 58 (Suppl.1) S -426 2015年04月
  • 心臓血管 大動脈解離におけるアディポネクチンの役割
    渡辺 芳樹; 宮川 繁; 福嶌 五月; 前田 法一; 斎藤 充弘; 鳥飼 慶; 上野 高義; 戸田 宏一; 倉谷 徹; 下村 伊一郎; 澤 芳樹 日本外科学会定期学術集会抄録集 115回 OP -2 2015年04月
  • マウスのウイルス性心筋炎モデルにおいて、アディポネクチン欠損が生存率と心臓・膵に与える影響(第2報)
    岩本 龍哉; 宇野 彩; 福井 健司; 小澤 純二; 前田 法一; 船橋 徹; 岩橋 博見; 今川 彰久; 下村 伊一郎 糖尿病 58 (Suppl.1) S -425 2015年04月
  • 堰本 亮平; 前田 法一; 對馬 佑; 松田 圭介; 森 卓也; 福田 士郎; 中辻 秀朗; 西澤 均; 岸田 堅; 菊田 順一; 船橋 徹; 石井 優; 下村 伊一郎 肥満研究 20 (Suppl.) 168 -168 2014年10月
  • 松田 圭介; 前田 法一; 藤島 裕也; 平田 歩; 森 卓也; 堰本 亮平; 小村 徳幸; 山岡 正弥; 井上 佳菜; 對馬 佑; 西澤 均; 船橋 徹; 下村 伊一郎 肥満研究 20 (Suppl.) 168 -168 2014年10月
  • 森 卓也; 小林 佳之; 前田 法一; 中村 雪子; 藤島 裕也; 松田 圭介; 船橋 徹; 島田 昌一; 下村 伊一郎 肥満研究 20 (Suppl.) 181 -181 2014年10月
  • 前田 法一; 下村 伊一郎 医学のあゆみ 250 (9) 723 -729 2014年08月
  • 炎症の制御を科学する(臨床) ST上昇型心筋梗塞におけるadiponectin値の推移
    夏川 知輝; 前田 法一; 澤野 宏隆; 一柳 裕司; 大津谷 耕一; 林 靖之; 船橋 徹; 下村 伊一郎; 甲斐 達朗 日本救急医学会雑誌 25 (8) 363 -363 2014年08月
  • アディポネクチンのT-カドヘリンを介した組織集積機構の解明
    松田 圭介; 前田 法一; 藤島 裕也; 平田 歩; 喜多 俊文; 森 卓也; 堰本 亮平; 山岡 正弥; 井上 佳菜; 對馬 佑; 西澤 均; 船橋 徹; 下村 伊一郎 日本動脈硬化学会総会プログラム・抄録集 46回 317 -317 2014年06月
  • 脂肪組織慢性炎症における免疫細胞の動態変化の解析
    堰本 亮平; 前田 法一; 對馬 佑; 松田 圭介; 森 卓也; 福田 士郎; 中辻 秀朗; 西澤 均; 岸田 堅; 菊田 順一; 船橋 徹; 石井 優; 下村 伊一郎 日本動脈硬化学会総会プログラム・抄録集 46回 320 -320 2014年06月
  • 對馬 佑; 西澤 均; 栩野 義博; 中辻 秀朗; 堰本 亮平; 長尾 博文; 白倉 尚; 加藤 賢太; 今泉 啓一郎; 高橋 洋之; 田村 みずほ; 前田 法一; 船橋 徹; 下村 伊一郎 メタボリックシンドローム 10 (1) 14 -21 2014年06月
  • 井上 佳菜; 前田 法一; 森 卓也; 山岡 正弥; 堰本 亮平; 對馬 佑; 西澤 均; 船橋 徹; 下村 伊一郎 日本内分泌学会雑誌 90 (1) 287 -287 2014年04月
  • 前田 法一; 森 卓也; 井上 佳菜; 山岡 正弥; 堰本 亮平; 對馬 佑; 西澤 均; 船橋 徹; 下村 伊一郎 日本内分泌学会雑誌 90 (1) 287 -287 2014年04月
  • 長尾 博文; 西澤 均; 樫根 晋; 岡田 拓也; 木村 武量; 平田 歩; 火伏 俊之; 津川 真美子; 福田 士郎; 前田 法一; 今川 彰久; 船橋 徹; 下村 伊一郎 日本内分泌学会雑誌 90 (1) 289 -289 2014年04月
  • 西澤 均; 對馬 佑; 栩野 義博; 中辻 秀朗; 堰本 亮平; 長尾 博文; 白倉 尚; 加藤 賢太; 今泉 啓一郎; 高橋 洋之; 田村 みずほ; 前田 法一; 船橋 徹; 下村 伊一郎 日本内分泌学会雑誌 90 (1) 349 -349 2014年04月
  • 2型糖尿病患者における、シタグリプチンの血中アディポネクチン濃度に対する影響(START-J study)
    火伏 俊之; 竹下 恵理子; 木村 武量; 平田 歩; 南 朋子; 中川 靖彦; 樫根 晋; 前田 法一; 岸田 堅; 西澤 均; 船橋 徹; 下村 伊一郎 糖尿病 57 (Suppl.1) S -169 2014年04月
  • ピオグリタゾン投与が有効であったインスリン抵抗性及び低アディポネクチン血症を伴うミトコンドリア糖尿病の1例
    二宮 浩世; 平田 歩; 中田 伸輔; 木村 武量; 坂本 扶美枝; 小澤 純二; 北村 哲宏; 安田 哲行; 前田 法一; 西澤 均; 今川 彰久; 船橋 徹; 下村 伊一郎 糖尿病 57 (Suppl.1) S -236 2014年04月
  • 2型糖尿病患者における内臓脂肪蓄積と睡眠リズムの関係
    福田 士郎; 平田 歩; 西澤 均; 長尾 博文; 木村 武量; 藤島 裕也; 井上 佳菜; 増田 重樹; 山岡 正弥; 樫根 晋; 小澤 純二; 岸田 堅; 前田 法一; 今川 彰久; 船橋 徹; 下村 伊一郎 糖尿病 57 (Suppl.1) S -286 2014年04月
  • 2型糖尿病患者の食嗜好の特徴と外来栄養指導における変化
    徳澤 千恵; 長井 直子; 志賀 佳織; 小笠 有加; 山本 美紀子; 山道 祐子; 福田 士郎; 平田 歩; 西澤 均; 前田 法一; 船橋 徹; 下村 伊一郎 糖尿病 57 (Suppl.1) S -342 2014年04月
  • アディポネクチンの心肥大抑制作用における、β-cateninシグナルの検討
    藤島 裕也; 松田 圭介; 井上 佳菜; 山岡 正弥; 平田 歩; 西澤 均; 前田 法一; 船橋 徹; 下村 伊一郎 糖尿病 57 (Suppl.1) S -408 2014年04月
  • 脂肪組織慢性炎症における免疫細胞の動態変化の解析
    堰本 亮平; 前田 法一; 岸田 堅; 中辻 秀朗; 福田 士郎; 西澤 均; 船橋 徹; 石井 優; 下村 伊一郎 糖尿病 57 (Suppl.1) S -446 2014年04月
  • アディポネクチンのT-カドヘリンを介した組織集積機構の解明
    松田 圭介; 前田 法一; 藤島 裕也; 平田 歩; 森 卓也; 堰本 亮平; 小村 徳幸; 山岡 正弥; 井上 佳菜; 對馬 佑; 西澤 均; 船橋 徹; 下村 伊一郎 糖尿病 57 (Suppl.1) S -446 2014年04月
  • 肥満脂肪細胞における時計遺伝子Period homolog 1(Per1)の発現制御
    山岡 正弥; 前田 法一; 堰本 亮平; 對馬 佑; 松田 圭介; 森 卓也; 井上 佳菜; 西澤 均; 船橋 徹; 下村 伊一郎 糖尿病 57 (Suppl.1) S -447 2014年04月
  • 肥満と末梢血単球数の関連性
    増田 重樹; 山岡 正弥; 前田 法一; 平田 歩; 西沢 均; 船橋 徹; 下村 伊一郎 糖尿病 57 (Suppl.1) S -447 2014年04月
  • 沖田 考平; 岩橋 博見; 小澤 純二; 岡内 幸義; 北村 哲宏; 岸田 堅; 西澤 均; 前田 法一; 大月 道夫; 船橋 徹; 今川 彰久; 下村 伊一郎 日本内分泌学会雑誌 90 (1) 265 -265 2014年04月
  • マウスのウイルス性心筋炎モデルにおいて、アディポネクチン欠損が生存率と心臓・膵に与える影響
    岩本 龍哉; 黒田 陽平; 福井 健司; 小澤 純二; 前田 法一; 船橋 徹; 岩橋 博見; 今川 彰久; 下村 伊一郎 糖尿病 57 (Suppl.1) S -325 2014年04月
  • アディポネクチンと大動脈解離の関係 大動脈解離のバイオマーカーとしての可能性
    渡辺 芳樹; 宮川 繁; 福嶌 五月; 前田 法一; 齋藤 充弘; 白川 幸俊; 上野 高義; 戸田 宏一; 倉谷 徹; 下村 伊一郎; 澤 芳樹 日本心臓血管外科学会雑誌 43 (Suppl.) 328 -328 2014年01月
  • 【どこが違う?どう違う? 図解でくらべる→わかる! 糖尿病の病態・治療・ケア】(第1章)糖尿病の病態・検査 メタボリックシンドロームと糖尿病
    前田 法一 糖尿病ケア (2013秋季増刊) 42 -49 2013年09月
  • 對馬 佑; 西澤 均; 栩野 義博; 中辻 秀朗; 堰本 亮平; 長尾 博文; 白倉 尚; 加藤 賢太; 今泉 啓一郎; 高橋 洋之; 田村 みずほ; 前田 法一; 船橋 徹; 下村 伊一郎 肥満研究 19 (Suppl.) 154 -154 2013年09月
  • 井上 佳菜; 前田 法一; 森 卓也; 山岡 正弥; 堰本 亮平; 對馬 佑; 西澤 均; 船橋 徹; 下村 伊一郎 肥満研究 19 (Suppl.) 164 -164 2013年09月
  • 福田 士郎; 平田 歩; 西澤 均; 長尾 博文; 木村 武量; 藤島 裕也; 井上 佳菜; 増田 重樹; 山岡 正弥; 樫根 晋; 小澤 純二; 岸田 堅; 前田 法一; 今川 彰久; 船橋 徹; 下村 伊一郎 肥満研究 19 (Suppl.) 202 -202 2013年09月
  • K. Inoue; N. Maeda; T. Mori; M. Yamaoka; R. Sekimoto; Y. Tsushima; H. Nishizawa; T. Funahashi; I. Shimomura DIABETOLOGIA 56 S310 -S311 2013年09月
  • 對馬 佑; 西澤 均; 中辻 秀朗; 堰本 亮平; 白倉 尚; 高橋 洋之; 藤島 裕也; 井上 佳菜; 松田 圭介; 森 卓也; 山岡 正弥; 平田 歩; 小村 徳幸; 岸田 堅; 前田 法一; 栩野 義博; 船橋 徹; 下村 伊一郎 痛風と核酸代謝 37 (1) 60 -60 2013年07月
  • 腹部肥満2型糖尿病患者における血管合併症と体重歴について
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  • 糖尿病血管合併症進展と健診受診歴の関連について
    木村 武量; 西澤 均; 火伏 俊之; 長尾 博文; 岡田 拓也; 津川 真美子; 嶺尾 郁夫; 福田 士郎; 平田 歩; 前田 法一; 今川 彰久; 船橋 徹; 下村 伊一郎 日本動脈硬化学会総会プログラム・抄録集 45回 197 -197 2013年06月
  • 2型糖尿病におけるC1q・アディポネクチン複合体と動脈硬化症の関連
    平田 歩; 岸田 堅; 井上 佳菜; 藤島 裕也; 西澤 均; 前田 法一; 船橋 徹; 下村 伊一郎 日本動脈硬化学会総会プログラム・抄録集 45回 197 -197 2013年06月
  • 脂肪組織におけるエフリンB1(EFNB1)の機能解析
    森 卓也; 前田 法一; 井上 佳菜; 山岡 正弥; 堰本 亮平; 對馬 佑; 松田 圭介; 西澤 均; 船橋 徹; 下村 伊一郎 日本動脈硬化学会総会プログラム・抄録集 45回 203 -203 2013年06月
  • 脂肪組織におけるXOR活性と肥満に伴う上昇
    對馬 佑; 西澤 均; 中辻 秀朗; 堰本 亮平; 白倉 尚; 山岡 正弥; 平田 歩; 岸田 堅; 前田 法一; 栩野 義博; 船橋 徹; 下村 伊一郎 日本動脈硬化学会総会プログラム・抄録集 45回 204 -204 2013年06月
  • 男性2型糖尿病患者での性腺機能低下症と血管合併症との関連、および糖代謝改善が性腺機能低下に及ぼす影響
    佐々木 周伍; 安田 哲行; 久保 典代; 辻 真由美; 藤澤 慶子; 嵩 龍一; 平田 歩; 小澤 純二; 北村 哲宏; 西澤 均; 前田 法一; 大月 道夫; 今川 彰久; 松岡 孝昭; 船橋 徹; 金藤 秀明; 下村 伊一郎 糖尿病 56 (Suppl.1) S -221 2013年04月
  • 肥満脂肪組織におけるS100A8の意義
    堰本 亮平; 前田 法一; 岸田 堅; 中辻 秀朗; 中川 徹; 船橋 徹; 下村 伊一郎 糖尿病 56 (Suppl.1) S -255 2013年04月
  • 脂肪組織におけるエフリンB1(EFNB1)の機能解析
    森 卓也; 前田 法一; 井上 佳菜; 山岡 正弥; 堰本 亮平; 対馬 佑; 西澤 均; 船橋 徹; 下村 伊一郎 糖尿病 56 (Suppl.1) S -256 2013年04月
  • 内臓脂肪蓄積で変動する新規遺伝子の解析
    井上 佳菜; 前田 法一; 森 卓也; 山岡 正弥; 堰本 亮平; 對馬 佑; 西澤 均; 船橋 徹; 下村 伊一郎 糖尿病 56 (Suppl.1) S -257 2013年04月
  • 2型糖尿病におけるC1q・アディポネクチン複合体と全身動脈硬化病変の検討
    平田 歩; 岸田 堅; 中辻 秀朗; 井上 佳菜; 西澤 均; 前田 法一; 船橋 徹; 下村 伊一郎 糖尿病 56 (Suppl.1) S -319 2013年04月
  • 肥満2型糖尿病の臨床像 血管合併症と体重歴
    長尾 博文; 西澤 均; 樫根 晋; 岡田 拓也; 木村 武量; 平田 歩; 火伏 俊之; 津川 真美子; 福田 士郎; 藤島 裕也; 小澤 純二; 前田 法一; 北村 哲宏; 安田 哲行; 沖田 考平; 今川 彰久; 船橋 徹; 下村 伊一郎 糖尿病 56 (Suppl.1) S -362 2013年04月
  • 内臓脂肪が末梢血球における炎症関連遺伝子発現に及ぼす影響
    前田 法一; 山岡 正弥; 船橋 徹; 下村 伊一郎 糖尿病 56 (Suppl.1) S -363 2013年04月
  • 内臓脂肪が末梢血遺伝子発現プロファイルに及ぼす影響
    山岡 正弥; 前田 法一; 樫根 晋; 中川 靖彦; 清水 亜紀; 船橋 徹; 下村 伊一郎 糖尿病 56 (Suppl.1) S -375 2013年04月
  • 脂肪組織におけるXOR活性の測定と肥満に伴う上昇
    對馬 佑; 西澤 均; 中辻 秀朗; 堰本 亮平; 白倉 尚; 高橋 洋之; 藤島 裕也; 井上 佳菜; 松田 圭介; 森 卓也; 山岡 正弥; 平田 歩; 小村 徳幸; 岸田 堅; 前田 法一; 栩野 義博; 船橋 徹; 下村 伊一郎 糖尿病 56 (Suppl.1) S -377 2013年04月
  • 血管内皮に存在するアディポネクチン蛋白の炎症状態における意義に関する研究
    小村 徳幸; 前田 法一; 森 卓也; 松田 圭介; 中辻 秀朗; 平田 歩; 木原 進士; 船橋 徹; 下村 伊一郎 糖尿病 56 (Suppl.1) S -434 2013年04月
  • アディポネクチンがT-カドヘリン発現に与える影響
    松田 圭介; 平田 歩; 小村 徳幸; 藤島 裕也; 西澤 均; 山岡 正弥; 井上 佳菜; 森 卓也; 對馬 佑; 堰本 亮平; 前田 法一; 船橋 徹; 下村 伊一郎 糖尿病 56 (Suppl.1) S -435 2013年04月
  • 肥満2型糖尿病患者の臨床像 動脈硬化症と食習慣
    福田 士郎; 平田 歩; 西澤 均; 長尾 博文; 木村 武量; 藤島 裕也; 樫根 晋; 小澤 純二; 北村 哲宏; 安田 哲行; 前田 法一; 徳澤 千恵; 山道 祐子; 山本 美紀子; 白波瀬 景子; 長井 直子; 安井 洋子; 今川 彰久; 船橋 徹; 下村 伊一郎 糖尿病 56 (Suppl.1) S -438 2013年04月
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    沖田 考平; 岩橋 博見; 小澤 純二; 岡内 幸義; 北村 哲宏; 岸田 堅; 西澤 均; 前田 法一; 大月 道夫; 船橋 徹; 今川 彰久; 下村 伊一郎 糖尿病 56 (Suppl.1) S -131 2013年04月
  • 劇症1型糖尿病患者における血清アディポネクチン濃度の検討
    岩本 龍哉; 今川 彰久; 岩橋 博見; 前田 法一; 船橋 徹; 下村 伊一郎; 小林 哲郎; 花房 俊昭 糖尿病 56 (Suppl.1) S -216 2013年04月
  • 脂肪組織におけるXOR活性の測定と肥満に伴う上昇
    對馬 佑; 西澤 均; 中辻 秀朗; 堰本 亮平; 白倉 尚; 高橋 洋之; 藤島 裕也; 井上 佳菜; 松田 圭介; 森 卓也; 山岡 正弥; 平田 歩; 小村 徳幸; 岸田 堅; 前田 法一; 栩野 義博; 船橋 徹; 下村 伊一郎 日本痛風・核酸代謝学会総会プログラム抄録集 46回 83 -83 2013年02月
  • 脂肪細胞の医学応用へ向けた試み〜脂肪細胞シート治療〜
    前田法一 神戸市医師会報 2 98 -100 2013年
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    前田法一、下村伊一郎 日本臨床増刊号「最新肥満症学」 72 (4) 236 -240 2013年
  • 下村 伊一郎; 細田 公則; 海老原 健; 山内 敏正; 前田 法一; 大内 乗有; 南野 徹 肥満研究 : 日本肥満学会誌 = Journal of Japan Society for the Study of Obesity 18 (3) 158 -159 2012年12月
  • Sokichi Kamata; Shigeru Miyagawa; Satsuki Fukushima; Atsuhiro Saito; Norikazu Maeda; Hiroyuki Nishi; Yasushi Yoshioka; Daisuke Yoshioka; Tetsuya Saito; Koichi Toda; Iichiro Shimomura; Yoshiki Sawa CIRCULATION 126 (21) 2012年11月
  • 鎌田 創吉; 宮川 繁; 福嶌 五月; 今西 悠紀子; 齋藤 充弘; 前田 法一; 下村 伊一郎; 澤 芳樹 Organ Biology 19 (2) 210 -210 2012年10月
  • 前田 法一; 船橋 徹; 下村 伊一郎 肥満研究 18 (Suppl.) 108 -108 2012年09月
  • 長尾 博文; 西澤 均; 樫根 晋; 岡田 拓也; 木村 武量; 平田 歩; 津川 真美子; 火伏 俊之; 岡内 幸義; 嶺尾 郁夫; 福田 士郎; 南 朋子; 藤島 裕也; 小澤 純二; 沖田 考平; 前田 法一; 今川 彰久; 船橋 徹; 下村 伊一郎 肥満研究 18 (Suppl.) 141 -141 2012年09月
  • 平田 歩; 岸田 堅; 中辻 秀朗; 清水 亜紀; 井上 佳菜; 西澤 均; 前田 法一; 船橋 徹; 下村 伊一郎 肥満研究 18 (Suppl.) 171 -171 2012年09月
  • 福田 士郎; 平田 歩; 岸田 堅; 中辻 秀朗; 清水 亜紀; 西澤 均; 前田 法一; 船橋 徹; 下村 伊一郎 肥満研究 18 (Suppl.) 171 -171 2012年09月
  • 膵腫瘤切除後14年の経過で内因性インスリン分泌能の枯渇を認めた自己免疫性膵炎の1例
    細川 吉弥; 小澤 純二; 樫根 晋; 北村 哲宏; 前田 法一; 大月 道夫; 沖田 考平; 岩橋 博見; 千原 剛; 今川 彰久; 下村 伊一郎 糖尿病 55 (9) 748 -748 2012年09月
  • ラット自己免疫関連性心筋炎における人工脂肪細胞細胞シート誘導免疫寛容処理移植による心臓へのアディポサイトカインの標的デリバリー法と機能回復(A Targeted Delivery of Adipocytokines into the Heart by Transplantation of Induced Adipocyte Cell-sheet Yields Immune-tolerance and Functional Recovery in Autoimmune-associated Myocarditis in Rat)
    鎌田 創吉; 宮川 繁; 福嶌 五月; 今西 悠紀子; 齋藤 充弘; 前田 法一; 下村 伊一郎; 澤 芳樹 日本心臓病学会誌 7 (Suppl.I) 245 -245 2012年08月
  • 動脈硬化を操る代謝シグナルネットワークの解明から治療へ アディポサイトカインと動脈硬化
    前田 法一; 船橋 徹; 下村 伊一郎 日本動脈硬化学会総会プログラム・抄録集 44回 143 -143 2012年07月
  • 前田 法一; 下村 伊一郎 日本臨床 70 (増刊3 最新臨床糖尿病学(上)) 486 -489 2012年05月
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  • 平田 歩; 前田 法一; 中辻 秀朗; 清水 亜紀; 船橋 徹; 下村 伊一郎 日本内分泌学会雑誌 88 (1) 332 -332 2012年04月
  • 井上 佳菜; 前田 法一; 樫根 晋; 小澤 純二; 沖田 考平; 今川 彰久; 船橋 徹; 下村 伊一郎 日本内分泌学会雑誌 88 (1) 357 -357 2012年04月
  • 佐々木 周伍; 安田 哲行; 宮下 和幸; 高原 充佳; 久保 典代; 辻 真由美; 藤澤 慶子; 嵩 龍一; 樫根 晋; 小澤 純二; 北村 哲宏; 西澤 均; 前田 法一; 沖田 孝平; 大月 道夫; 松岡 孝昭; 今川 彰久; 金藤 秀明; 船橋 徹; 下村 伊一郎 日本内分泌学会雑誌 88 (1) 376 -376 2012年04月
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  • PPARgammaアゴニスト・リボグリタゾンによるアディポネクチンおよびS100A8への効果
    前田 法一; 日生下 亜紀; 平田 歩; 中辻 秀朗; 木原 進士; 船橋 徹; 下村 伊一郎 糖尿病 55 (Suppl.1) S -114 2012年04月
  • 肥満2型糖尿病において、Liraglutideが体重・食行動および血糖コントロールに与える影響
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  • 肥満2型糖尿病におけるリラグルチドの内臓脂肪・食欲に及ぼす短期的効果の検討
    井上 佳菜; 前田 法一; 樫根 晋; 小澤 純二; 沖田 考平; 今川 彰久; 船橋 徹; 下村 伊一郎 糖尿病 55 (Suppl.1) S -197 2012年04月
  • 外来2型糖尿病患者における頸動脈プラークと各種血中パラメーターの関連性
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  • 男性2型糖尿病患者での性腺機能低下症に関する検討
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  • 腹部肥満2型糖尿病の臨床像
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  • 先端巨大症における耐糖能メカニズムの解明 75g経口ブドウ糖負荷試験での検討
    大月 道夫; 北村 哲宏; 安田 哲行; 前田 法一; 沖田 考平; 今川 彰久; 金藤 秀明; 船橋 徹; 齋藤 洋一; 下村 伊一郎 糖尿病 55 (Suppl.1) S -248 2012年04月
  • 当院2型糖尿病外来患者の全身血管エコーの意義
    平田 歩; 岸田 堅; 清水 亜紀; 中辻 秀朗; 井上 佳菜; 前田 法一; 船橋 徹; 下村 伊一郎 日本内科学会雑誌 101 (Suppl.) 231 -231 2012年02月
  • 日本人肥満2型糖尿病患者におけるリラグルチドの有用性と食行動
    前田法一 DITN 419 5 -5 2012年
  • 下村 伊一郎; 小川 佳宏; 高橋 将文; 菅波 孝祥; 薄井 勲; 久米 真司; 前田 法一 肥満研究 : 日本肥満学会誌 = Journal of Japan Society for the Study of Obesity 17 (3) 161 -162 2011年12月
  • 小野寺 俊晴; 玉田 大介; 大月 道夫; 北村 哲宏; 細川 吉弥; 小澤 純二; 安田 哲行; 前田 法一; 沖田 考平; 今川 彰久; 金藤 秀明; 船橋 徹; 押野 悟; 斉藤 洋一; 下村 伊一郎 日本内分泌学会雑誌 87 (3) 953 -953 2011年12月
  • 玉田 大介; 大月 道夫; 北村 哲宏; 小野寺 俊晴; 細川 吉弥; 小澤 純二; 安田 哲行; 前田 法一; 沖田 考平; 今川 彰久; 金藤 秀明; 船橋 徹; 辻村 晃; 下村 伊一郎 日本内分泌学会雑誌 87 (3) 980 -980 2011年12月
  • 井上 佳菜; 小澤 純二; 船橋 徹; 中田 幸子; 光井 絵理; 北村 哲宏; 前田 法一; 岸田 堅; 大月 道夫; 沖田 考平; 岩橋 博見; 今川 彰久; 下村 伊一郎 日本内分泌学会雑誌 87 (3) 929 -929 2011年12月
  • 前田 法一; 火伏 俊之 Adiposcience 8 (1) 25 -31 2011年10月
  • 前田 法一; 船橋 徹; 下村 伊一郎 肥満研究 17 (Suppl.) 123 -123 2011年09月
  • 平田 歩; 前田 法一; 中辻 秀朗; 清水 亜紀; 船橋 徹; 下村 伊一郎 肥満研究 17 (Suppl.) 136 -136 2011年09月
  • 井上 佳菜; 前田 法一; 樫根 晋; 小澤 純二; 沖田 考平; 今川 彰久; 船橋 徹; 下村 伊一郎 肥満研究 17 (Suppl.) 144 -144 2011年09月
  • 平田 歩; 岸田 堅; 中辻 秀朗; 清水 亜紀; 前田 法一; 船橋 徹; 下村 伊一郎 肥満研究 17 (Suppl.) 197 -197 2011年09月
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  • 前田 法一; 日生下 亜紀; 平田 歩; 中辻 秀朗; 木原 進士; 船橋 徹; 下村 伊一郎 肥満研究 17 (Suppl.) 207 -207 2011年09月
  • 前田 法一; 下村 伊一郎 日本内科学会雑誌 100 (4) 911 -916 2011年04月
  • 当院糖尿病外来患者の全身血管エコーの特徴
    平田 歩; 岸田 堅; 中辻 秀朗; 清水 亜紀; 前田 法一; 船橋 徹; 下村 伊一郎 糖尿病 54 (Suppl.1) S -354 2011年04月
  • 肥満者における内臓脂肪蓄積と末梢血発現遺伝子プロファイルの解析
    山岡 正弥; 前田 法一; 樫根 晋; 中川 靖彦; 清水 亜紀; 船橋 徹; 下村 伊一郎 糖尿病 54 (Suppl.1) S -357 2011年04月
  • 小村 徳幸; 木原 進士; 前田 法一; 船橋 徹; 下村 伊一郎 日本内分泌学会雑誌 87 (1) 356 -356 2011年04月
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    田渕 優希子; 大月 道夫; 北村 哲宏; 井上 佳奈; 小澤 純二; 前田 法一; 沖田 考平; 岩橋 博見; 今川 彰久; 金藤 秀明; 船橋 徹; 下村 伊一郎 糖尿病 54 (Suppl.1) S -142 2011年04月
  • 高度肥満合併糖尿病患者における腹腔鏡下袖状胃切除術の効果
    沖田 考平; 山岡 正弥; 岩本 龍哉; 岡内 幸義; 樫根 晋; 北村 哲宏; 小澤 純二; 前田 法一; 大月 道夫; 岩橋 博見; 宮崎 安弘; 瀧口 修司; 土岐 祐一郎; 前田 和久; 船橋 徹; 今川 彰久; 下村 伊一郎 糖尿病 54 (Suppl.1) S -203 2011年04月
  • リラグルチド投与により食行動の変化を認めた2型糖尿病の1例
    大月 道夫; 北村 哲宏; 倉敷 有紀子; 前田 法一; 小澤 純二; 沖田 考平; 岩橋 博見; 今川 彰久; 金藤 秀明; 船橋 徹; 下村 伊一郎 糖尿病 54 (Suppl.1) S -243 2011年04月
  • 肥満・非肥満2型糖尿病患者の病態分類によるインクレチン関連薬の有効性の検討
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  • シタグリプチン投与によるインスリン治療を中止し得た肥満2型糖尿病患者の1例
    岩本 龍哉; 岡内 幸義; 樫根 晋; 小澤 純二; 北村 哲宏; 前田 法一; 大月 道夫; 沖田 考平; 岩橋 博見; 今川 彰久; 下村 伊一郎 糖尿病 54 (3) 203 -203 2011年03月
  • グリセロールチャネル分子アクアポリン7の心臓における意義
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  • 清水 亜紀; 前田 法一; 船橋 徹 Adiposcience 7 (2) 144 -148 2010年12月
  • Yukiko Imanishi; Shigeru Miyagawa; Norikazu Maeda; Iichiro Shimomura; Yoshiki Sawa CIRCULATION 122 (21) 2010年11月
  • 前田 法一 肥満研究 16 (Suppl.) 98 -98 2010年09月
  • 中辻 秀朗; 前田 法一; 火伏 俊之; 清水 亜紀; 平田 歩; 黒田 陽平; 岸田 堅; 木原 進士; 船橋 徹; 下村 伊一郎 肥満研究 16 (Suppl.) 127 -127 2010年09月
  • 小村 徳幸; 木原 進士; 前田 法一; 船橋 徹; 下村 伊一郎 肥満研究 16 (Suppl.) 143 -143 2010年09月
  • 平田 歩; 前田 法一; 中辻 秀朗; 日生下 亜紀; 木原 進士; 船橋 徹; 下村 伊一郎 肥満研究 16 (Suppl.) 150 -150 2010年09月
  • 前田 法一; 木原 進士; 船橋 徹; 下村 伊一郎 Therapeutic Research 31 (6) 789 -793 2010年06月
  • 前田 法一; 火伏 俊之; 船橋 徹 Vascular Medicine 6 (2) 162 -167 2010年04月
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  • 心臓におけるグリセロールチャネル分子アクアポリン7の発現制御
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  • 脂肪肝臓におけるDEPP(decidual protein induced by progesterone)発現の意義
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  • 新規チアゾリジン誘導体リボグリタゾンのアディポネクチンに与える影響
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  • 平田 歩; 前田 法一; 日生下 亜紀; 火伏 俊之; 藤田 幸一; 岡田 拓也; 木原 進士; 船橋 徹; 下村 伊一郎 日本内分泌学会雑誌 86 (1) 139 -139 2010年03月
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  • Norikazu Maeda; Tohru Funahashi; Iichiro Shimomura ENDOCRINE JOURNAL 57 S316 -S317 2010年03月
  • S. Kamata; T. Sakaguchi; S. Miyagawa; Y. Yoshikawa; T. Yatnauchi; S. Saito; Y. Shudo; Y. Imanishi; A. Saito; N. Maeda; T. Ueno; T. Kuratani; Y. Sawa JOURNAL OF HEART AND LUNG TRANSPLANTATION 29 (2) S47 -S47 2010年02月
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  • Juichi Fukushima; Yoshihiro Kamada; Hitoshi Matsumoto; Yuichi Yoshida; Hisao Ezaki; Takayo Takemura; Mina Hamano; Shinichi Kiso; Norikazu Maeda; Shinji Kihara; Tohru Funahashi; Iichiro Shimomura; Norio Hayashi HEPATOLOGY 50 (4) 1180A -1180A 2009年10月
  • 前田 法一; 船橋 徹; 下村 伊一郎 肥満研究 15 (Suppl.) 115 -115 2009年09月
  • 平田 歩; 前田 法一; 日生下 亜紀; 火伏 俊之; 藤田 幸一; 岡田 拓也; 木原 進士; 船橋 徹; 下村 伊一郎 肥満研究 15 (Suppl.) 249 -249 2009年09月
  • 栗山 洋; 黒田 陽平; 木原 進士; 前田 法一; 岸田 堅; 船橋 徹; 下村 伊一郎 人間ドック 24 (2) 544 -544 2009年08月
  • 前田 法一; 船橋 徹; 下村 伊一郎 日本内分泌学会雑誌 85 (1) 248 -248 2009年04月
  • 火伏 俊之; 前田 法一; 中辻 秀朗; 藤田 幸一; 日生下 亜紀; 岸田 堅; 木原 進士; 船橋 徹; 下村 伊一郎 日本内分泌学会雑誌 85 (1) 284 -284 2009年04月
  • 藤田 幸一; 小澤 純二; 前田 法一; 沖田 考平; 岩橋 博見; 木原 進士; 大村 素子; 中村 正; 船橋 徹; 白井 厚治; 山村 卓; 下村 伊一郎 日本内分泌学会雑誌 85 (1) 343 -343 2009年04月
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  • 心臓におけるグリセロールチャネルの意義
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  • Depp(decidual protein induced by progesterone)遺伝子発現は絶食により上昇、インスリン添加により低下する
    黒田 陽平; 栗山 洋; 木原 進士; 前田 法一; 岸田 堅; 西澤 均; 船橋 徹; 下村 伊一郎 糖尿病 52 (Suppl.1) S -262 2009年04月
  • インスリン抵抗性における脂肪細胞ミネラルコルチコイド受容体の意義
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  • 樫根 晋; 岸田 堅; 船橋 徹; 大月 道夫; 沖田 考平; 平田 歩; 藤田 幸一; 中川 靖彦; 前田 法一; 岩橋 博見; 木原 進士; 中村 正; 吉田 良子; 松澤 佑次; 下村 伊一郎 日本内分泌学会雑誌 85 (1) 368 -368 2009年04月
  • 著明な発疹性黄色腫を伴った高中性脂肪血症の一例
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  • 山田 拓哉; 荒木 浩士; 鎌田 佳宏; 西原 承緒; 渡部 健二; 木曽 真一; 前田 法一; 木原 進士; 船橋 徹; 下村 伊一郎; 筒井 秀作; 林 紀夫 日本消化器病学会雑誌 106 (臨増総会) A248 -A248 2009年03月
  • メタボリックシンドロームの病態解明と「低アディポネクチン血症」概念の樹立
    船橋 徹; 前田 法一; 岸田 堅; 西澤 均; 木原 進士; 藤田 幸一; 中川 靖彦; 丹波 祥子; 岡内 幸義 代謝異常治療研究基金研究業績集 36 1 -17 2009年01月
  • 福島 寿一; 鎌田 佳宏; 木曽 真一; 松本 仁; 竹村 貴代; 江崎 久男; 佐治 雪子; 吉田 雄一; 前田 法一; 井倉 技; 筒井 秀作; 田村 信司; 木原 進士; 船橋 徹; 下村 伊一郎; 林 紀夫 日本消化器病学会雑誌 105 (臨増大会) A833 -A833 2008年09月
  • 山田 拓哉; 西原 承緒; 荒木 浩士; 鎌田 佳宏; 渡部 健二; 木曽 真一; 筒井 秀作; 前田 法一; 木原 進士; 舟橋 徹; 下村 伊一郎; 林 紀夫 日本消化器病学会雑誌 105 (臨増大会) A894 -A894 2008年09月
  • アディポネクチンはアンジオテンシンII誘導性の心筋線維化を抑制する
    藤田 幸一; 前田 法一; 火伏 俊之; 西澤 均; 西田 誠; 日生下 亜紀; 木原 進士; 下村 伊一郎; 船橋 徹 日本臨床分子医学会学術総会プログラム・抄録集 45回 61 -61 2008年07月
  • Adiponectinと老化
    前田 法一; 下村 伊一郎 内分泌・糖尿病科 26 (6) 583 -587 2008年06月
  • F. Matsuura; H. Oku; M. Koseki; K. Yamamoto; J. C. Sandoval; M. Kawase; D. Masuda; T. Ohama; N. Maeda; M. Ishigami; M. Nishida; K. Hirano; S. Kihara; M. Hori; I. Shimomura; S. Yamashita ATHEROSCLEROSIS SUPPLEMENTS 9 (1) 24 -24 2008年05月
  • 藤田 幸一; 前田 法一; 火伏 俊之; 西澤 均; 西田 誠; 日生下 亜紀; 木原 進士; 下村 伊一郎; 船橋 徹 日本内分泌学会雑誌 84 (1) 187 -187 2008年04月
  • 糸球体過負荷モデルにおけるアディポネクチンの意義(アディポネクチン欠損マウスにおける検討より)
    小村 徳幸; 大橋 浩二; 木原 進士; 中川 靖彦; 藤田 幸一; 前田 法一; 下村 伊一郎; 船橋 徹 糖尿病 51 (Suppl.1) S -297 2008年04月
  • アディポネクチンはアンジオテンシンII誘導性の心筋線維化を抑制する
    藤田 幸一; 前田 法一; 火伏 俊之; 西澤 均; 西田 誠; 日生下 亜紀; 木原 進士; 下村 伊一郎; 船橋 徹 糖尿病 51 (Suppl.1) S -309 2008年04月
  • フィブラートは脂肪細胞PPARα活性化を介してアディポネクチンを上昇させる
    日生下 亜紀; 前田 法一; 熊田 全裕; 火伏 俊之; 藤田 幸一; 西澤 均; 木原 進士; 下村 伊一郎; 船橋 徹 糖尿病 51 (Suppl.1) S -310 2008年04月
  • Matsuura Fumihiko; Oku Hiroyuki; Koseki Masahiro; Yamamoto Kazumi; Masuda Daisaku; Ohama Tohru; Maeda Norikazu; Kihara Shinji; Hori Masatsugu; Shimomura Iichiro; Yamashita Shizuya Circulation journal : official journal of the Japanese Circulation Society 72 398 -398 2008年03月
  • 前田 法一 The Lipid 19 (1) 4 -10 2008年01月
  • メタボリックシンドロームの病態解明と「低アディポネクチン血症」概念の樹立
    船橋 徹; 木原 進士; 栗山 洋; 前田 法一; 西澤 均; 岸田 堅; 岡田 拓也; 岡内 幸義; 小村 徳幸 代謝異常治療研究基金研究業績集 35 1 -14 2008年01月
  • Y. Kuroda; H. Kuriyama; K. Kishida; N. Maeda; H. Nishizawa; S. Kihara; T. Funahashi; I. Shimomura DIABETOLOGIA 50 S307 -S308 2007年09月
  • Pre-hypertension(前高血圧)の病態と臨床的意義 有田町疫学研究・トランスレーショナル研究からみた軽症高血圧の病態
    北風 政史; 金 智隆; 朝倉 正紀; 浅沼 博司; 船橋 徹; 前田 法一; 松沢 佑次; 北村 惣一郎; 友池 仁暢 Journal of Cardiology 50 (Suppl.I) 149 -149 2007年08月
  • フィブラートがアディポネクチンに及ぼす影響の分子的解明
    日生下 亜紀; 前田 法一; 熊田 全裕; 火伏 俊之; 藤田 幸一; 西澤 均; 木原 進士; 下村 伊一郎; 船橋 徹 日本臨床分子医学会学術総会プログラム・抄録集 44回 76 -76 2007年07月
  • 【メタボリックシンドロームup to date】トピックス アクアポリン・アディポース
    前田 法一; 火伏 俊之; 船橋 徹 日本医師会雑誌 136 (特別1) S306 -S307 2007年06月
  • Aki Hiuge; Norikazu Maeda; Masahiro Kumada; Koichi Fujita; Hitoshi Nishizawa; Shinji Kihara; Iichiro Shimomura; Alexander Tenenbaum; Tohru Funahashi DIABETES 56 A352 -A352 2007年06月
  • 【メタボリックシンドローム研究の進展】メタボリックシンドロームとアクアポリン
    前田 法一 内分泌・糖尿病科 24 (5) 425 -432 2007年05月
  • 日生下 亜紀; 前田 法一; 熊田 全裕; 火伏 俊之; 藤田 幸一; 西澤 均; 木原 進士; 下村 伊一郎; 船橋 徹 日本内分泌学会雑誌 83 (1) 89 -89 2007年04月
  • 倉田 晃文; 西澤 均; 前田 法一; 木原 進士; 園田 美奈; 岡田 拓也; 藤田 幸一; 日生下 亜紀; 下村 伊一郎; 船橋 徹 日本内分泌学会雑誌 83 (1) 107 -107 2007年04月
  • 藤田 幸一; 西澤 均; 前田 法一; 船橋 徹; 下村 伊一郎; 島袋 充生 日本内分泌学会雑誌 83 (1) 184 -184 2007年04月
  • 前田 法一; 船橋 徹 内科 98 (6) 1087 -1090 2006年12月
  • 火伏 俊之; 前田 法一; 船橋 徹; 下村 伊一郎 肥満研究 12 (3) 251 -254 2006年12月
  • Juichi Fukushima; Shinji Tamura; Yoshihiro Kamada; Hitoshi Matsumoto; Shinichi Kiso; Koji Fukui; Takumi Igura; Norikazu Maeda; Shinji Kihara; Tohru Funahashi; Iichiro Shimomura; Norio Hayashi HEPATOLOGY 44 (4) 669A -669A 2006年10月
  • K. Fujita; N. Maeda; K. Ohashi; H. Nishizawa; M. Nishida; S. Kihara; I. Shimomura; T. Funahashi EUROPEAN HEART JOURNAL 27 689 -690 2006年08月
  • A. Hiuge; N. Maeda; S. Kihara; M. Kumada; H. Nishizawa; M. Sonoda; I. Shimomura; T. Funahashi EUROPEAN HEART JOURNAL 27 690 -690 2006年08月
  • 前田 法一 肥満研究 12 (1) 9 -18 2006年04月
  • 火伏 俊之; 前田 法一; 船橋 徹; 長澤 安曇; 岸田 堅; 栗山 洋; 中村 正; 木原 進士; 松澤 佑次; 下村 伊一郎 日本内分泌学会雑誌 82 (1) 94 -94 2006年04月
  • 鎌田 佳宏; 田村 信司; 林 紀夫; 松本 仁; 福島 寿一; 佐治 雪子; 福井 浩司; 木曽 真一; 前田 法一; 木原 進士; 船橋 徹; 松澤 祐次; 下村 伊一郎 日本消化器病学会雑誌 103 (臨増総会) A147 -A147 2006年03月
  • 【高血圧 その発症・進展と代謝異常】新しい概念 メタボリックシンドロームの基礎病態 脂肪組織の変化を中心に
    前田 法一; 下村 伊一郎 カレントテラピー 23 (12) 8 -12 2005年11月
  • 火伏 俊之; 前田 法一; 船橋 徹; 長澤 安曇; 岸田 堅; 栗山 洋; 中村 正; 木原 進士; 松澤 佑次; 下村 伊一郎 肥満研究 11 (Suppl.) 154 -154 2005年09月
  • アクアポリンアディポースの生体内における機能解析
    火伏 俊之; 前田 法一; 船橋 徹; 長澤 安曇; 岸田 堅; 栗山 洋; 中村 正; 木原 進士; 松澤 佑次; 下村 伊一郎 日本臨床分子医学会学術総会プログラム・抄録集 42回 98 -98 2005年07月
  • クッパー細胞に対するアディポネクチンの抗炎症作用
    松本 仁; 田村 信司; 鎌田 佳宏; 木曽 真一; 佐治 雪子; 前田 法一; 船橋 徹; 下村 伊一郎 日本臨床分子医学会学術総会プログラム・抄録集 42回 123 -123 2005年07月
  • 松本 仁; 田村 信司; 鎌田 佳宏; 木曽 真一; 佐治 雪子; 福島 寿一; 前田 法一; 船橋 徹; 篠村 恭久; 下村 伊一郎 肝臓 46 (Suppl.1) A172 -A172 2005年05月
  • アディポネクチンのマクロファージにおけるIL-10・TIMP-1発現増加作用の解明
    熊田 全裕; 木原 進士; 大内 乗有; 岡本 芳久; 大橋 浩二; 前田 法一; 前田 和久; 船橋 徹; 下村 伊一郎; 松澤 佑次 日本臨床分子医学会記録 41 31 -31 2005年05月
  • 生活習慣病における医学,薬学の萠芽的研究 脂肪細胞特異的分泌蛋白アディポネクチンと生活習慣病 アディポネクチン・ノックアウトマウスおよび過剰発現マウスを用いた研究
    前田 法一 医科学応用研究財団研究報告 22 225 -229 2005年02月
  • 脂肪組織由来血漿蛋白アディポネクチンによる血管障害抑制機序の解明及び血管病の進展抑制に関する研究
    木原 進士; 熊田 全裕; 大内 乗有; 岡本 芳久; 流谷 裕幸; 前田 法一; 船橋 徹; 松澤 佑次 代謝異常治療研究基金研究業績集 32 41 -47 2005年01月
  • 前田 法一; 下村 伊一郎 Medical Practice 21 (12) 2051 -2054 2004年12月
  • 前田 法一; 下村 伊一郎 Medical Technology 32 (13) 1474 -1475 2004年12月
  • H Matsumoto; S Tamura; Y Kamada; S Kiso; Y Saji; N Maeda; T Yokota; Y Shinomura; T Funahashi; Shimomura, I HEPATOLOGY 40 (4) 699A -699A 2004年10月
  • アディポネクチン欠損マウスとメタボリックシンドローム
    前田 法一; 下村 伊一郎; 木原 進士; 船橋 徹; 松澤 佑次 Diabetes Frontier 15 (5) 734 -734 2004年10月
  • 前田 法一; 船橋 徹; 下村 伊一郎 Adiposcience 1 (3) 247 -257 2004年10月
  • 松本 仁; 田村 信司; 鎌田 佳宏; 木暮 真一; 佐治 雪子; 前田 法一; 横田 貴史; 船橋 徹; 篠村 恭久; 下村 伊一郎 肝臓 45 (Suppl.2) A454 -A454 2004年09月
  • 熊田 全裕; 木原 進士; 大内 乗有; 岡本 芳久; 大橋 浩二; 前田 法一; 前田 和久; 下村 伊一郎; 船橋 徹; 松澤 佑次 肥満研究 10 (Suppl.) 120 -120 2004年09月
  • 火伏 俊之; 長澤 安曇; 岸田 堅; 前田 法一; 流谷 裕幸; 西澤 均; 下村 伊一郎; 木原 進士; 船橋 徹; 福井 健介; 小嶋 真紀子; 高松 清治; 脇 昌子; 松澤 佑次 肥満研究 10 (Suppl.) 134 -134 2004年09月
  • 鎌田 佳宏; 田村 信司; 松本 仁; 佐治 雪子; 木曽 真一; 福井 浩司; 前田 法一; 木原 進士; 宮川 潤一郎; 篠村 恭久; 船橋 徹; 松澤 佑次; 下村 伊一郎 肥満研究 10 (Suppl.) 159 -159 2004年09月
  • 前田 法一; 船橋 徹; 下村 伊一郎 Diabetes Frontier 15 (4) 474 -479 2004年08月
  • アディポネクチンのマクロファージにおけるIL-10・TIMP-1発現増加作用の解明
    熊田 全裕; 木原 進士; 大内 乗有; 岡本 芳久; 大橋 浩二; 前田 法一; 前田 和久; 船橋 徹; 下村 伊一郎; 松澤 佑次 日本臨床分子医学会学術総会プログラム・抄録集 41回 39 -39 2004年07月
  • アディポサイエンスの最前線 アディポサイトカインとメタボリックシンドローム
    前田 法一; 船橋 徹 日本動脈硬化学会総会プログラム・抄録集 36回 163 -163 2004年07月
  • アディポネクチンのマクロファージにおける抗炎症機序
    熊田 全裕; 木原 進士; 大内 乗有; 大橋 浩二; 前田 法一; 流谷 裕幸; 火伏 俊之; 前田 和久; 船橋 徹; 松澤 佑次 日本動脈硬化学会総会プログラム・抄録集 36回 221 -221 2004年07月
  • 【メタボリックシンドロームの分子標的】アディポネクチン
    前田 法一; 船橋 徹; 下村 伊一郎 BIO Clinica 19 (7) 488 -493 2004年06月
  • 前田 法一; 鎌田 佳宏; 松本 仁; 西澤 均; 流谷 裕幸; 岡本 芳久; 木曽 真一; 木原 進士; 田村 信司; 船橋 徹; 松澤 佑次 日本内分泌学会雑誌 80 (1) 115 -115 2004年04月
  • 熊田 全裕; 木原 進士; 大内 乗有; 岡本 芳久; 大橋 浩二; 火伏 俊之; 前田 法一; 流谷 裕幸; 前田 和久; 船橋 徹; 松澤 佑次 日本内分泌学会雑誌 80 (1) 115 -115 2004年04月
  • 前田 法一; 船橋 徹 肥満研究 10 (1) 22 -30 2004年04月
  • アディポネクチンのKupffer細胞におけるTNF-α分泌抑制効果 培養Kupffer細胞及びアディポネクチンKOマウスを用いた急性肝障害モデルでの検討
    松本 仁; 田村 信司; 鎌田 佳宏; 木曽 真一; 佐治 雪子; 前田 法一; 木原 進士; 篠村 恭久; 船橋 徹; 松澤 佑次 肝臓 45 (Suppl.1) A139 -A139 2004年04月
  • 脂肪組織由来血漿蛋白アディポネクチンによる血管障害抑制機序の解明及び血管病の進展抑制に関する研究
    木原 進士; 大内 乗有; 有田 幸生; 岡本 芳久; 流谷 裕幸; 前田 法一; 船橋 徹; 松澤 佑次 代謝異常治療研究基金研究業績集 31 31 -38 2004年01月
  • 前田 法一; 西澤 均; 岸田 堅; 松田 守弘; 流谷 裕幸; 下村 伊一郎; 木原 進士; 船橋 徹; 松澤 佑次 肥満研究 9 (Suppl.) 78 -78 2003年10月
  • N Maeda; H Nishizawa; K Kishida; M Matsuda; Shimomura, I; S Kihara; T Funahashi; Y Matsuzawa ATHEROSCLEROSIS SUPPLEMENTS 4 (2) 48 -48 2003年09月
  • N Maeda; H Nishizawa; K Kishida; M Matsuda; Shimomura, I; S Kihara; T Funahashi; Y Matsuzawa ATHEROSCLEROSIS SUPPLEMENTS 4 (2) 105 -105 2003年09月
  • N Maeda; H Nishizawa; K Kishida; M Matsuda; Y Okamoto; Shimomura, I; S Kihara; T Funahashi; Y Matsuzawa DIABETOLOGIA 46 A79 -A79 2003年08月
  • N Maeda; K Kishida; H Nishzawa; M Matsuda; H Nagaretani; S Kihara; Shimomura, I; T Funahashi; Y Matsuzawa DIABETES 52 A24 -A25 2003年06月
  • 鎌田 佳宏; 田村 信司; 木曽 真一; 吉田 雄一; 福井 浩司; 前田 法一; 西沢 均; 流谷 裕幸; 岡本 芳久; 木原 進士; 宮川 潤一郎; 船橋 徹; 松澤 佑次 肝臓 44 (Suppl.1) A102 -A102 2003年04月
  • 前田 法一; 西澤 均; 岸田 堅; 松田 守弘; 流谷 裕幸; 岡本 芳久; 熊田 全裕; 大橋 浩二; 大内 乗有; 木原 進士; 下村 伊一郎; 船橋 徹; 松澤 佑次 日本内分泌学会雑誌 79 (1) 121 -121 2003年04月
  • アディポネクチンノックアウトマウスにおけるインスリン抵抗性
    前田 法一; 岸田 堅; 西澤 均; 松田 守弘; 流谷 裕幸; 大内 乗有; 木原 進士; 下村 伊一郎; 船橋 徹; 松澤 佑次 糖尿病 46 (Suppl.1) S134 -S134 2003年04月
  • アディポネクチンとCRPとの関連 血中及び脂肪組織での検討
    大内 乗有; 熊田 全裕; 木原 進士; 大橋 浩二; 中村 正; 流谷 裕幸; 岡本 芳久; 西澤 均; 岸田 堅; 前田 法一; 船橋 徹; 松澤 佑次 糖尿病 46 (Suppl.1) S181 -S181 2003年04月
  • 冠動脈疾患におけるアディポネクチン遺伝子変異の解析
    大橋 浩二; 大内 乗有; 木原 進士; 船橋 徹; 中村 正; 流谷 裕幸; 熊田 全裕; 岡本 芳久; 西澤 均; 岸田 堅; 前田 法一; 荻原 俊男; 松澤 佑次 糖尿病 46 (Suppl.1) S181 -S181 2003年04月
  • アディポネクチン遺伝子異常のメタボリックシンドロームにおける意義
    流谷 裕幸; 近藤 秀彦; 下村 伊一郎; 大橋 浩二; 熊田 全裕; 前田 法一; 西澤 均; 岸田 堅; 松田 守弘; 高橋 雅彦; 大内 乗有; 木原 進士; 船橋 徹; 松澤 佑次 糖尿病 46 (Suppl.1) S204 -S204 2003年04月
  • ホルモンによるアディポネクチン産生調節作用
    西澤 均; 下村 伊一郎; 岸田 堅; 前田 法一; 流谷 裕幸; 木原 進士; 中村 正; 船橋 徹; 松澤 佑次 糖尿病 46 (Suppl.1) S255 -S255 2003年04月
  • Ouchi Noriyuki; Kihara Shinji; Kumada Masahiro; Arita Yukio; Ohashi Koji; Okamoto Yoshihisa; Maeda Norikazu; Kishida Ken; Nagaretani Hiroyuki; Nakamura Tadashi; Funahashi Tohru; Matsuzawa Yuji Circulation journal : official journal of the Japanese Circulation Society 67 447 -448 2003年03月
  • Maeda Norikazu; Kishida Ken; Nishizawa Hitoshi; Nagaretani Hiroyuki; Matsuda Morihiro; Ohuchi Noriyuki; Kihara Shinji; Shimomura Iichiro; Funahashi Tohru; Matsuzawa Yuji Circulation journal : official journal of the Japanese Circulation Society 67 196 -196 2003年03月
  • Nagaretani Hiroyuki; Kondo Hidehiko; Shimomura Iichiro; Kumada Masahiro; Maeda Norikazu; Nishizawa Hitoshi; Kishida Ken; Matsuda Morihiro; Takahashi Masahiko; Ouchi Noriyuki; Kihara Shinji; Kawamoto Toshiharu; Sumitsuji Satoru; Funahashi Tohru; Matsuzawa Yuji Circulation journal : official journal of the Japanese Circulation Society 67 123 -123 2003年03月
  • アディポネクチン 代謝異常症候群のKey Molecule
    前田 法一; 下村 伊一郎; 岸田 堅; 西澤 均; 松田 守弘; 流谷 裕幸; 大内 乗有; 木原 進士; 船橋 徹; 松沢 佑次 日本内科学会雑誌 92 (Suppl.) 127 -127 2003年02月
  • 脂肪組織由来血漿蛋白アディポネクチンによる血管障害抑制機序の解明及び血管病の進展抑制に関する研究
    木原 進士; 大内 乗有; 有田 幸生; 岡本 芳久; 流谷 裕幸; 前田 法一; 船橋 徹; 松澤 佑次 代謝異常治療研究基金研究業績集 30 22 -28 2003年01月
  • 前田 法一 肥満研究 8 (Suppl.) 68 -68 2002年09月
  • S Matsumoto; K Kishida; Shimomura, I; A Yamada; N Maeda; H Nagaretani; M Matsuda; H Nishizawa; S Kihara; S Yamashita; S Tamura; S Kawata; T Funahashi; Y Matsuzawa BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 295 (2) 571 -571 2002年07月
  • 脂肪組織由来分泌因子アディポネクチンの抗動脈硬化作用
    松田 守弘; 下村 伊一郎; 前田 法一; 有田 幸生; 大内 乗有; 木原 進士; 船橋 徹; 松澤 佑次 動脈硬化 (34回抄集) 135 -135 2002年06月
  • 前田 法一; 松田 守弘; 有田 幸生; 下村 伊一郎; 木原 進士; 船橋 徹; 松澤 佑次 日本内分泌学会雑誌 78 (1) 84 -84 2002年04月
  • N Maeda; M Takahashi; T Funahashi; S Kihara; H Nishizawa; K Kishida; H Nagaretani; M Matsuda; R Komuro; N Ouchi; H Kuriyama; K Hotta; T Nakamura; Shimomura, I; Y Matsuzawa Diabetes 50 (9) 2094 -2099 2001年09月
  • 抗動脈硬化因子アディポネクチンの減量,チアゾリジン誘導体による血中濃度増加
    丸川 聡子; 堀田 紀久子; 今川 彰久; 樫根 晋; 前田 法一; 高橋 雅彦; 福井 健司; 岩橋 博見; 山縣 和也; 中島 弘; 宮川 潤一郎; 船橋 徹 糖尿病 44 (5) 439 -439 2001年05月
  • 動脈硬化の分子機構における脂肪細胞の意義
    木原 進士; 有田 幸生; 大内 乗有; 岡本 芳久; 熊田 全裕; 前田 法一; 流谷 裕幸; 松山 晃文; 酒井 尚彦; 平岡 久豊 Japanese Circulation Journal 65 (Suppl.I-B) 49 -49 2001年03月
  • 脂肪細胞由来抗動脈硬化因子アディポネクチンの遺伝子解析
    流谷 裕幸; 高橋 雅彦; 前田 法一; 有田 幸生; 大内 乗有; 木原 進士; 中村 正; 船橋 徹; 松澤 佑次 糖尿病 44 (Suppl.1) S22 -S22 2001年03月
  • 脂肪細胞由来抗動脈硬化因子アディポネクチンの発現分泌調節 インスリン,デキサメサゾン,TNF-αの影響
    高橋 雅彦; 前田 法一; 木原 進士; 中村 正; 船橋 徹; 松澤 佑次 糖尿病 44 (Suppl.1) S87 -S87 2001年03月
  • 脂肪細胞由来因子アディポネクチンの糖尿病,動脈硬化における意義
    熊田 全裕; 木原 進士; 堀田 紀久子; 有田 幸生; 大内 乗有; 岡本 芳久; 前田 法一; 中村 正; 船橋 徹; 松澤 佑次 糖尿病 44 (Suppl.1) S22 -S22 2001年03月
  • 脂肪細胞由来抗動脈硬化因子アディポネクチンの発現調節 チアゾリジン誘導体の影響
    前田 法一; 高橋 雅彦; 堀田 紀久子; 下村 伊一郎; 木原 進士; 中村 正; 船橋 徹; 松澤 佑次 糖尿病 44 (Suppl.1) S86 -S86 2001年03月
  • 前田 法一; 丸川 聡子; 高橋 雅彦; 大内 乗有; 堀田 紀久子; 木原 進士; 中村 正; 今川 彰久; 岩橋 博見; 山縣 和也 日本内分泌学会雑誌 76 118 -118 2000年12月
  • 流谷 裕幸; 高橋 雅彦; 前田 法一; 有田 幸生; 大内 乗有; 木原 進士; 中村 正; 山下 静也; 船橋 徹; 松澤 佑次 肥満研究 6 (Suppl.) 92 -92 2000年09月
  • 前田 法一; 高橋 雅彦; 堀田 紀久子; 木原 進士; 中村 正; 船橋 徹; 山下 静也; 松澤 佑次 肥満研究 6 (Suppl.) 138 -138 2000年09月
  • 3T3-L1細胞の脂肪蓄積にともなう細胞骨格の変化とゲルゾリンの関与
    西田 誠; 前田 法一; 流谷 裕幸; 高橋 雅彦; 栗山 洋; 木原 進士; 宮川 潤一郎; 船橋 徹; 山下 静也; 松澤 佑次 動脈硬化 28 (Suppl.) 184 -184 2000年05月
  • 増田 大作; 大屋 健; 前田 法一; 丸山 貴生; 中村 正; 船橋 徹; 山下 静也; 松澤 佑次 Japanese Circulation Journal 64 (Suppl.II) 796 -796 2000年04月
  • 西田 誠; 高橋 雅彦; 前田 法一; 栗山 洋; 木原 進士; 宮川 潤一郎; 船橋 徹; 山下 静也; 松澤 佑次 日本内分泌学会雑誌 76 (1) 118 -118 2000年04月
  • 脂肪細胞由来分子アディポネクチン 減量療法,チアゾリジン誘導体が血中濃度に及ぼす効果
    前田 法一; 堀田 紀久子; 木原 進士; 高橋 雅彦; 田中 幸代; 船橋 徹; 山下 静也; 栗山 洋; 中村 正; 松澤 佑次 動脈硬化 27 (Suppl.1) 149 -149 1999年11月
  • 西田 誠; 前田 法一; 流谷 裕幸; 高橋 雅彦; 栗山 洋; 木原 進士; 宮川 潤一郎; 船橋 徹; 山下 静也; 松沢 佑次 肥満研究 5 (Suppl.) 146 -146 1999年10月
  • 前田 法一; 堀田 紀久子; 木原 進士; 高橋 雅彦; 田中 幸代; 船橋 徹; 山下 静也; 栗山 洋; 中村 正; 松澤 佑次 肥満研究 5 (Suppl.) 148 -148 1999年10月
  • 前田 法一; 熊田 全裕; 岸本 正彦; 西田 義治; 安冨 保治; 平岡 久豊 心臓 31 (10) 725 -730 1999年10月
  • 自己免疫関連膵炎の合併にて血糖コントロール悪化をきたしたNIDDMの1例
    岸本 正彦; 大塚 章人; 野村 祐介; 熊田 全裕; 名波 正義; 松岡 哲朗; 前田 法一; 丸川 聡子; 長田 明; 上野 玲 糖尿病 42 (9) 790 -790 1999年09月
  • 前田 法一; 丸川 聡子; 野村 祐介; 熊田 全裕; 松岡 哲郎; 西田 義治; 平岡 久豊 Japanese Circulation Journal 63 (Suppl.II) 768 -768 1999年08月
  • DDD pacemakerと薬物療法の併用が著効したCarotid Sinus Syncopeの1例
    前田 法一; 熊田 全裕; 西田 義治; 平岡 久豊 Japanese Circulation Journal 62 (Suppl.III) 969 -969 1999年02月
  • 著明な心不全をきたしたミトコンドリア遺伝子異常を有する糖尿病の1例
    熊田 全裕; 前田 法一; 岸本 正彦; 西田 義治; 山根 光量; 平岡 久豊 Japanese Circulation Journal 62 (Suppl.II) 737 -737 1998年08月
  • 心筋症を伴うミトコンドリア異常を有する糖尿病の一例
    熊田 全裕; 前田 法一; 岸本 正彦; 西田 義治; 山根 光量; 大塚 章人; 平岡 久豊; 多田 秀敏; 市原 紀久雄 糖尿病 41 (7) 553 -553 1998年07月
  • 前田 法一 Japanese Circulation Journal 61 (Suppl.III) 849 -849 1998年03月
  • 前田 法一; 平岡 久豊; 中村 正 呼吸と循環 45 (6) 613 -617 1997年06月
  • 前田 法一; 松浦 文彦; 中川 理; 平岡 久豊; 中村 正; 船橋 徹; 山下 静也; 竹村 芳; 松沢 佑次 Japanese circulation journal 60 773 -773 1997年01月

受賞

  • 2014年 大阪大学総長奨励賞
  • 2012年 日本内分泌学会研究奨励賞
  • 2009年 日本肥満学会学術奨励賞
  • 2006年 第32回日本心臓財団研究奨励賞
  • 2005年 平成17年度 岡本研究奨励賞
     JPN
  • 2005年 The 3rd Metabolic Syndrome Conference Metab.S 若手研究奨励賞
     JPN
  • 2005年 第21回 井上研究奨励賞
     JPN
  • 2005年 Research Award on Molecular and Cellular Cardiology
  • 2004年 第2回 日本心臓財団動脈硬化Update 優秀賞
     JPN
  • 2003年 63th. Scientific meeting of American Diabetes Association Travel Grant
  • 2003年 日本肥満学会若手研究奨励賞
     JPN
  • 2003年 日本内分泌学会若手研究奨励賞
     JPN
  • 2003年 Yamanouchi Foundation for Research on Metabolic Disorders
  • 2003年 Mitsubishi Pharma Research Foundation

共同研究・競争的資金等の研究課題

  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2023年04月 -2026年03月 
    代表者 : 前田 法一; 西澤 均; 藤島 裕也; 福田 士郎
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2023年04月 -2026年03月 
    代表者 : 西澤 均; 前田 法一; 藤島 裕也; 喜多 俊文; 福田 士郎
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2022年04月 -2025年03月 
    代表者 : 喜多 俊文; 前田 法一; 西澤 均; 藤島 裕也; 福田 士郎
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2020年07月 -2023年03月 
    代表者 : 下村 伊一郎; 前田 法一; 西澤 均; 喜多 俊文; 藤島 裕也
     
    間葉系幹細胞(MSCs)を用いた急性発症1型糖尿病の治療法を開発した。近年、抗がん剤として免疫チェックポイント阻害薬(ICI)が注目され、種々の悪性腫瘍に対して使用が拡大している。ICIの副作用として種々の自己免疫疾患が挙げられるが、中でも急性発症1型糖尿病は、膵β細胞を完全に失うことで血糖コントロールは極めて不良となり、合併症の進行、患者のQOL、予後が著しく損なわれる。癌は2040年には年間2890万人が新たに罹患し、その36.1%はICIが適応されると予想されており、ICI投薬患者の約0.5%に1型糖尿病の発症を認めることより、年間約5.2万人に糖尿病が新規発症すると予測されるが、未だ有効な治療法は確立していない。 通常は糖尿病を発症しない雄性NOD/ShiJclマウスに、抗マウスPD-L1モノクローナル中和抗体を投与することで、ICIに誘発される急性発症1型糖尿病が発症するモデルを構築した。本モデルにヒト脂肪由来MSC(hMSC) を投与して糖尿病の発症率および血糖推移を検討し、その有効性を確認し、MSCsの産生するエクソソームがその作用を担う可能性を示した(Diabetologia in Press、特願2021-26666)。 また、アディポネクチン結合パートナーであるT-cadherinは血中にエクソソームの構成成分としてのみならず、大部分は遊離タンパクとして存在し、糖尿病患者群の中でHBA1cなどのパラメータと有意な相関を示すことを明らかにし(Fukuda et al., JCEM2021)、ストレプトゾシン惹起糖尿病モデル等のインスリン枯渇状態で増加し、膵β細胞の増殖を促進する新しい液性因子であることを明らかにした(Okita et al. 投稿中)。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2019年04月 -2022年03月 
    代表者 : 喜多 俊文; 前田 法一; 西澤 均; 藤島 裕也
     
    アディポネクチンは脂肪から分泌される善玉タンパクで、様々な生活習慣病から私たちを守っている因子です。これまでアディポRという受容体が作用を担っていると考えられてきましたが、実はT-カドヘリンという特別な膜タンパクに結合して、細胞の中に入り、エクソソームという粒子を産生させることで機能していることがわかってきました。この働きは幹細胞治療にも重要で、重症心不全や癌の免疫療法で起こってくるような1型糖尿病の治療に応用できる可能性があります。また、T-カドヘリンは細胞から遊離して血中にもあり、糖尿病のような状態で増加して、膵臓のインスリン産生細胞の増殖を助ける働きがあることもわかってきました。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2019年04月 -2022年03月 
    代表者 : 前田 法一; 西澤 均; 喜多 俊文; 藤島 裕也
     
    アディポネクチンおよびその結合タンパクであるT-カドヘリン欠損マウスを用いて、腎虚血再灌流モデルを作製し解析した。結果、アディポネクチン/T-カドヘリンシステムは毛細血管のバリア機能の保持、血管周皮細胞の恒常性維持に重要な役割を果たしていることが明らかになった。 可溶性T-カドヘリンを測定できるELISAを確立し、血中には3種類の可溶性T-カドヘリン(130-kDa, 100-kDa, 30-kDa)が存在することを明らかにした。2型糖尿病や急性心筋梗塞患者で、可溶性T-カドヘリン濃度が臨床パラメーターと相関することを見出し、新たなバイオマーカーとなる可能性を示した。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2019年04月 -2022年03月 
    代表者 : 西澤 均; 前田 法一; 藤島 裕也
     
    尿酸産生阻害薬の標的であるXOR(キサンチン酸化還元酵素、xanthine oxidoreductase)に着目し、本研究では、最近測定が可能となった血漿XOR活性の病態生理学的意義を検討した。肥満2型糖尿病患者および高度肥満症の外科手術前後において血漿XOR活性は肝酵素と強く連関すること、脂肪肝モデルマウスで血中XOR活性および新生内膜増殖が亢進し、XOR阻害剤で抑制されることを報告した。これらの結果より脂肪肝で上昇する血中XOR活性が動脈硬化症に連関することが示唆された。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2018年04月 -2021年03月 
    代表者 : 下村 伊一郎; 福原 淳範; 喜多 俊文; 加藤 恒; 前田 法一; 小林 祥子
     
    生理的なアディポネクチンは主にT-カドヘリンという細胞表面タンパクに特異的に働き、エクソソームという小胞の産生を促進することで、血管内皮の保護、骨格筋の再生や腎保護などに働き、また間葉系幹細胞を用いた心不全モデルの細胞治療効果を担うことがわかりました。また、血中遊離T-カドヘリンの存在を証明し、定量EIAを構築した。 脂肪・血管分泌因子Favine欠損マウスはアポE欠損による動脈硬化が進行し、石灰化と血栓形成も認めました。Favine欠損マウス大動脈の遺伝子発現変化はヒトの不安定動脈硬化症の遺伝子発現変化と酷似することが分かりました。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2016年04月 -2019年03月 
    代表者 : 前田 法一; 西澤 均; 喜多 俊文
     
    脂肪細胞から分泌されるアディポネクチンは、細胞膜上のT-カドヘリンを介して、動脈硬化の進展を抑制していることを明らかにした。また、アディポネクチンとT-カドヘリンが結合する分子機構を明らかにし、アディポネクチンは高い親和性でT-カドヘリンに結合することが分かった。 アディポネクチンの多彩な臓器保護作用を一元的に説明しうるメカニズムとして、アディポネクチンがT-カドヘリンを介してエクソソーム分泌を有意に上昇させることを明らかにした。 GPI-アンカー切断酵素であるGPI-PLDが、糖尿病状態で特に肝臓で上昇することを明らかにし、GPI-PLD阻害薬は新規糖尿病治療薬になりうる事を示した。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2016年04月 -2019年03月 
    代表者 : 喜多 俊文; 前田 法一; 西澤 均
     
    脂肪から分泌される善玉タンパク、アディポネクチンは心血管・骨格筋にT-カドヘリンという細胞表面タンパクに特徴的なメカニズムで強く結合し、その細胞内に集積し、エクソソームと呼ばれる小胞の産生を促進することで、組織の保護、再生の促進に寄与していることを明らかにしました。 エクソソームは細胞の老廃物などを排出する機能と細胞同士のコミュニケーションを図る機能があり、アディポネクチンのエクソソーム産生促進作用は、善玉タンパクとされる所以を初めて明確に説明するだけでなく、今後の様々な臓器傷害治療・予防に応用されます。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2015年04月 -2018年03月 
    代表者 : 下村 伊一郎; 福原 淳範; 前田 法一
     
    アディポネクチンはT-カドヘリンを介して血管傷害部位に集積し、抗動脈硬化作用を発揮すること、アディポネクチンはT-カドヘリンの特定の部位に高い結合性を有することを示した。アディポネクチンはT-カドヘリンを介してエクソソーム産生を亢進させる新たな作用を見いだした。 GPI-PLDは肝DAG量を正に制御する重要な酵素であり、糖尿病状態では発現亢進することから、新たな治療ターゲットとなる可能性がある。Favineは脂肪細胞の脂肪細胞分化と脂肪合成を正に制御することを示した。Favineは血管における炎症作用にも関与することが示唆される。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2015年04月 -2018年03月 
    代表者 : 西澤 均; 船橋 徹; 前田 法一; 永森 收志
     
    肥満脂肪組織での代謝異常の全容は明らかではない。当教室では以前、肥満脂肪組織から尿酸分泌が亢進していることをマウスモデルで報告した(J.Biol.Chem.2013)。本研究ではヒト脂肪組織検体を用い、ヒト脂肪組織においてはXORの発現は限定的で主にヒポキサンチンとしてプリン代謝物を産生・分泌し、低酸素状態で亢進していることを見出した(Obesity, in press)。また、メタボローム解析により、肥満脂肪組織ではTCAサイクルが亢進しそれに伴いグルタミン酸産生が増加し、それがアディポネクチン分泌抑制、脂肪細胞のインスリン抵抗性を惹起することを報告した(J.Biol.Chem.2017)。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2016年04月 -2017年03月 
    代表者 : 山岡 正弥; 前田 法一; 西澤 均; 喜多 俊文
     
    メタボリックシンドロームにおけるサルコペニアに関する研究は、大阪大学医学部附属病院内分泌代謝内科及び川崎病院糖尿病内分泌内科に入院した症例を対象に評価を行っている。主に筋肉量や筋力を測定するとともに代謝パラメーターや骨密度、血中アディポネクチン値などとの相関関係を解析している。現在約130名エントリーしており、今後も症例数を増やしながら解析を行っていく。 末梢血遺伝子発現プロファイルの解析の1つとして、住友病院内分泌代謝内科入院症例(代謝異常非合併肥満者、耐糖能障害症例)を対象に解析を行った。本検討は、全例腹部CTによる内臓脂肪及び皮下脂肪面積を定量評価できている点において極めて精度の高いものである。結果、内臓脂肪は1,354個の遺伝子プローブの発現に影響を与えるのに対し、皮下脂肪や体格指数(BMI)は全く末梢血遺伝子発現に影響を与えなかった。また、年齢あるいは性別は、それぞれ625個、52個の遺伝子プローブ発現に影響することを示した。特に内臓脂肪蓄積に伴い、KLF10の発現が顕著に減少しており、メタボリックシンドローム発症病態における新たな分子を見出した。 さらに、Gene ontology解析の結果、炎症、酸化ストレス、免疫応答、脂質代謝や糖代謝に関連する遺伝子群への影響は、内臓脂肪は約20-30%の遺伝子に影響するのに対して、皮下脂肪は3-5%しか影響を与えないことも明らかにした。以上、論文報告を行った。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2014年04月 -2017年03月 
    代表者 : 船橋 徹; 前田 法一; 西澤 均
     
    内臓脂肪蓄積は糖代謝・脂質代謝・血圧の異常に加え、アディポネクチン分泌不全を始めとするアディポサイトカイン異常や易炎症性、易血栓性を伴い動脈硬化性疾患にいたる。本研究は1)内臓脂肪蓄積特異的な流血中の炎症細胞発現遺伝子を同定し、2)生体イメージング技術により炎症細胞を可視化し脂肪蓄積過程で脂肪細胞と炎症細胞の相互作用をダイナミックに捉え、3)内臓脂肪と皮下脂肪組織の代謝物の比較分析も合わせ行って、内臓脂肪の生物学をおしすすめ、急増する過栄養病態への対策に貢献しようとするものである。本年度は、1)血球発現遺伝子解析については、肥満・糖尿病教育入院をおこない、内臓脂肪、皮下脂肪量の評価もおこなった対象をエントリーし、順次全血球細胞からのRNAを抽出してマイクロアレイ解析の準備をすすめた。マウスにおける実験医学研究としては、アディポネクチン欠損(Adipo-/-)マウスと野生型(WT)マウスの血球細胞を分析し、両者に差がある可能性を認めたため詳細な検討をすすめている。2)生体イメージング法を用いた脂肪組織における免疫細胞動態については、LysMEGFP、CD11cEYFPTgマウスに高脂肪高蔗糖(HF/HS)食を負荷して、LysMEGFP陽性細胞が負荷早期から活発に活動することを観察した。脂肪細胞から分泌されるS100A8が重要な役割を果たす可能性が示された。LysMEGFP陽性細胞の大部分は末血では好中球であるのに対し脂肪組織ではマクロファージが多くを占めた。またこれら炎症細胞の動態におよぼすアディポネクチンの意義を明らかにするためにLysMEGFP-Adipo-/-およびCD11cEYFP-Adipo-/-マウスの作製を進めた。3)内臓脂肪組織、皮下脂肪組織の代謝物解析については、肥満モデルマウスから腸間膜・皮下脂肪を採取し基礎検討を行った。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2013年04月 -2016年03月 
    代表者 : 前田 法一; 船橋 徹
     
    アディポネクチンは脂肪細胞から特異的に分泌され血液中に存在する蛋白である。アディポネクチンがある特定の組織・細胞に集積し、臓器保護作用を発揮することを明らかにした。アディポネクチンはT-カドヘリンに結合し、T-カドヘリンが高発現している大動脈・心臓・骨格筋に集積していた。特に、大動脈において詳細な検討を行った。定常状態でアディポネクチンはすでに血管内皮細胞に集積していた。動脈硬化部位では、アディポネクチンは内皮細胞のみならず、内膜に遊走してきた合成型平滑筋細胞や内皮に接着した単球表面にもその集積を認めた。アディポネクチン/T-カドヘリンは生体内の恒常性維持に必要なシステムと考えられる。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2012年04月 -2015年03月 
    代表者 : 下村 伊一郎; 大月 道夫; 福原 淳範; 西澤 均; 前田 法一
     
    アディポネクチン(Adp)は心血管系と動脈硬化病変の内皮細胞、増殖型平滑筋細胞、単球に検出された。T-カドヘリン欠損マウスでは、組織のAdp蛋白が減少し、血中濃度は上昇した。Adpの組織集積はT-カドヘリンを介した。C1q-Adp複合体ELISAを確立した。複合体はBMIや脂肪面積と相関し、動脈硬化と関連した。Adpの心筋線維化抑制作用の一部はβカテニン経路の阻害を介した。Favine(Fvn)の遺伝子改変マウスの解析結果から、Fvnは脂肪細胞分化と脂肪合成を促進する作用を示した。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2010年04月 -2015年03月 
    代表者 : 船橋 徹; 岸田 堅; 前田 法一; 西澤 均
     
    肥満形成過程早期より脂肪組織マクロファージはダイナミックに活動しS100A8阻害により抑制された。アディポネクチンは定常状態より脂肪組織間質細胞や大動脈内皮細胞に結合しており、肥満では脂肪組織間質への集積が増加、動脈硬化ではプラーク内平滑筋細胞に集積した。大動脈局在にはT-cadherinが必須であった。急性冠症候群では低アディポネクチン血症にも関わらず流血中でC1qとの複合体濃度が増加していた。アディポネクチンは新たな概念の内分泌因子と考えられた。2型糖尿病症例で全身血管エコーや内臓脂肪評価を行いメタボリックシンドローム型は特に多発性動脈硬化病変やアディポサイトカイン異常と関連していた。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2010年 -2012年 
    代表者 : 木原 進士; 船橋 徹; 前田 法一
     
    アディポネクチンの結合蛋白質としてシスタチン C を同定した。またアディポネクチンがマクロファージにおいてVascular Endothelial Growth Factor-C を制御していることを明らかにした。 シスタチン C は、血管内皮細胞においてアディポネクチンによる抗炎症作用を阻害し、アディポネクチンの血中からのクリアランスを抑制した。腎不全例において血中アディポネクチン濃度は高値であるにもかかわらず動脈硬化が進行する機序として、腎不全で増加するシスタチン C が アディポネクチンと結合して血管代謝機構を障害することが示唆された。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2010年 -2012年 
    代表者 : 前田 法一; 船橋 徹
     
    アディポネクチン欠損マウスへ外因的に投与したアディポネクチンは心臓に集積し、心保護作用を発揮した。マイクロアレイ解析の結果、マウス白色脂肪組織にて新たなアディポサイトカインとして S100A8 を同定した。アディポネクチンの発現調節に関わる因子として、グルココルチコイドを新たに同定し、その調節機序を明らかにした。
  • 日本学術振興会:科学研究費助成事業
    研究期間 : 2004年 -2005年 
    代表者 : 前田 法一
     
    アクアポリン・アディポース(aquaporin adipose;AQPap)ノックアウトマウスの解析 前年度に引き続き、AQPap ノックアウトマウス(AQPap KO)の解析を継続した。体重変化を24週齢まで観察すると、AQPap KOは12週齢以降になると有意に肥満を呈することを見出した。このとき、野生型マウス(WT)に比し耐糖能障害および全身性のインスリン抵抗性、アディポサイトカインの分泌異常を伴っていた。白色脂肪組織の形態学的検討により、AQPap KOは肥大化した脂肪細胞の増殖が観察された。さらに、体重差のない若週齢から高脂肪・高蔗糖食負荷を行うと速やかにAQPap KOは重篤なインスリン抵抗性を伴う肥満を呈した。次に、AQPap KOが肥満を来す原因につき、体重差のない若週齢のマウスを用いて検討を加えた。まず、酸素消費量および呼吸商を測定したが両マウス間で差はなく、脂肪組織、肝臓、骨格筋における肥満・糖尿病関連遺伝子を調べたが明らかな差は見い出せなかった。次に、グリセロール代謝の律速酵素であるグリセロールキナーゼの活性を調べたところ、白色脂肪組織のグリセロールキナーゼ活性がAQPap KOで有意に上昇していた。そこで、3T3-L1脂肪細胞にRNAiを用いてAQPapをknockdownすると、細胞内グリセロール含量が増加し、グリセロールキナーゼ潜性が上昇し、オレイン酸取り込みも増加し、中性脂肪含量が増加した。すなわち、AQPapは脂肪細胞のグリセロールチャネルとして機能し、本分子の欠損により細胞外へのグリセロール放出が障害され、グリセロールキナーゼ活性が誘導され、最終的に脂肪細胞が肥大し肥満を呈することを明らかにした。
  • メタボリックシンドローム発症における分子基盤の解明
  • 内臓脂肪症候群
  • 動脈硬化
  • 虚血性心疾患
  • Metabolic syndrome
  • Visceral Fat Syndrome
  • Artheriosclerosis
  • Ischemic Heart Disease

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