Elucidation of the role of FSTL3/Activin axis in the development of obesity-induced diabetes

• Project/Area Number: 24249053
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Metabolomics
• Research Institution: The University of Tokyo
• Principal Investigator: UEKI Kohjiro 東京大学, 医学部附属病院, 特任教授 (00396714)
• Co-Investigator(Renkei-kenkyūsha): OKAZAKI Yukiko 東京大学, 医学部附属病院, 助教 (30422299) ; SUWANAI Hirotsugu 東京大学, 医学部附属病院, 助教 (60624939) ; SASAKO Takayoshi 東京大学, 医学部附属病院, 特任助教 (20550429) ; KOBAYASI Masatoshi 東京大学, 医学部附属病院, 特任助教 (30396725)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥45,110,000 (Direct Cost: ¥34,700,000、Indirect Cost: ¥10,410,000); Fiscal Year 2014: ¥13,000,000 (Direct Cost: ¥10,000,000、Indirect Cost: ¥3,000,000); Fiscal Year 2013: ¥12,870,000 (Direct Cost: ¥9,900,000、Indirect Cost: ¥2,970,000); Fiscal Year 2012: ¥19,240,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥4,440,000)
• Keywords: 糖尿病 / 肥満 / アディポカイン / インスリン抵抗性 / インスリン分泌 / トランスレーショナルリサーチ

Outline of Final Research Achievements

We have identified FSTL3 as an adipokine whose expression starts increasing at the very early stage of obesity. Adenovirus-mediated gene transfer of FSTL3 in mice resulted in impaired glucose tolerance, while suppression of FSTL3 by an antisense oligonucleotide or a neutralizing antibody improved it in obese diabetic mice. On the other hand, Adenovirus-mediated gene transfer or administration of Activin B, which is known to bind to FSTL3, markedly ameliorated impaired glucose homeostasis in obese diabetic mice. We have found that this beneficial effect of Activin B is mediated through enhancement of insulin secretion, suppression of hepatic gluconeogenesis and improvement of insulin sensitivity. These data suggest that modulation of FSTL3/Activin axis may be a promising therapeutic strategy for the treatment of obesity-induced diabetes.

Research Products

• [Journal Article] Insulin receptor substrate-2 (irs2) in endothelial cells plays a crucial role in insulin secretion (2015)
  • Author(s): Hashimoto, S. Kubota, N. Sato, H. Sasaki, M. Takamoto, I. Kubota, T. Nakaya, K. Noda, M. Ueki, K. Kadowaki, T.
  • Journal Title: Diabetes Volume: 64 Issue: 3 Pages: 876-886
  • DOI: 10.2337/db14-0432
  • Peer Reviewed
• [Journal Article] Ethnic differences in insulin sensitivity, beta-cell function, and hepatic extraction between Japanese and Caucasians: a minimal model analysis (2014)
  • Author(s): Moller, J. B. Dalla Man, C. Overgaard, R. V. Ingwersen, S. H. Tornoe, C. W. Pedersen, M. Tanaka, H. Ohsugi, M. Ueki, K. Lynge, J. Vasconcelos, N. M. Pedersen, B. K. Kadowaki, T. Cobelli, C.
  • Journal Title: J Clin Endocrinol Metab Volume: 99 Issue: 11 Pages: 4273-4280
  • DOI: 10.1210/jc.2014-1724
  • Peer Reviewed
• [Journal Article] Deregulation of Pancreas-Specific Oxidoreductin ERO1beta in the Pathogenesis of Diabetes Mellitus (2014)
  • Author(s): Awazawa, M. Futami, T. Sakada, M. Kaneko, K. Ohsugi, M. Nakaya, K. Terai, A. Suzuki, R. Koike, M. Uchiyama, Y. Kadowaki, T. Ueki, K.
  • Journal Title: Mol Cell Biol Volume: 34 Issue: 7 Pages: 1290-1299
  • DOI: 10.1128/mcb.01647-13
  • Peer Reviewed / Open Access
• [Journal Article] A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. (2013)
  • Author(s): Okada-Iwabu M, Yamauchi T, Iwabu M, Honma T, Hamagami K, Matsuda K, Yamaguchi M, Tanabe H, Kimura-Someya T, Shirouzu M, Ogata H, Tokuyama K, Ueki K, Nagano T, Tanaka A, Yokoyama S and Kadowaki T.
  • Journal Title: Nature Volume: 503 Issue: 7477 Pages: 493-499
  • DOI: 10.1038/nature12656
  • Peer Reviewed
• [Presentation] Activin/FSTL3による糖代謝制御機構 (2015)
  • Author(s): 岡崎由希子、岩根亜弥、小林直樹、笹子敬洋、諏訪内浩紹、小林正稔、窪田直人、山内敏正、原 一雄、門脇 孝、植木浩二郎
  • Organizer: 第29回日本糖尿病・肥満動物学会年次学術集会
  • Place of Presentation: 京都市
  • Year and Date: 2015-02-13 – 2015-02-14
  • Invited
• [Presentation] ヒト脂肪組織発現解析を用いた病態特異的アディポカインの検索 (2014)
  • Author(s): 岡﨑由希子、岩根亜弥、小林直樹、笹子敬洋、諏訪内浩紹、小林正稔、戸田郷太郎、添田光太郎、澤田知伸、坂田道教、原一雄、窪田直人、山内敏正、門脇孝、植木浩二郎
  • Organizer: 第29回 日本糖尿病合併症学会
  • Place of Presentation: 千代田区
  • Year and Date: 2014-10-03 – 2014-10-04
• [Presentation] ヒト脂肪組織発現解析を用いた病態特異的アディポカインの検索 (2014)
  • Author(s): 岡﨑由希子、岩根亜弥、小林直樹、笹子敬洋、諏訪内浩紹、小林正稔、原一雄、窪田直人、山内敏正、門脇孝、植木浩二郎
  • Organizer: 第19回 日本肥満学会主催 アディポサイエンス・シンポジウム
  • Place of Presentation: 豊中市
  • Year and Date: 2014-08-23
• [Presentation] 肥満と老化に抗して 生活習慣病に克つ (2014)
  • Author(s): 植木浩二郎
  • Organizer: 第32回内分泌代謝学サマーセミナー
  • Place of Presentation: 河口湖町
  • Year and Date: 2014-07-10 – 2014-07-12
  • Invited
• [Presentation] ヒト脂肪組織発現解析を用いた病態特異的アディポカインの検索 (2014)
  • Author(s): 岡崎由希子、岩根亜弥、笹子敬洋、坂田道教、諏訪内浩紹、梅原敏弘、小林直樹、小林正稔、窪田直人、原 一雄、山内敏正、吉村浩太郎、光嶋勲、油谷浩幸、門脇 孝、植木浩二郎
  • Organizer: 第57回日本糖尿病学会年次学術集会
  • Place of Presentation: 大阪市
  • Year and Date: 2014-05-22 – 2014-05-24
• [Presentation] Molecular mechanisms involved in obesity-induced diabetes (2014)
  • Author(s): Kohjiro Ueki
  • Organizer: DEBATE 2014
  • Place of Presentation: Hotel Le Meridien, Bangalore, India
  • Invited
• [Presentation] Identification of a novel adipokine involved in the development of the Metabolic Syndrome (2013)
  • Author(s): Yukiko Okazaki, Kohjiro Ueki, Aya Iwane, Takayoshi Sasako, Michinori Sakada, Toshihiro Umehara, Hirotsugu Suwanai, Masatoshi Kobayashi, Motoharu Awazawa, Naoki Kobayashi, Kazuo Hara, Matthias Blueher, Takashi Kadowaki
  • Organizer: 73th Scientific Sessions of the American Diabetes Association
  • Place of Presentation: The Moscone Center, Chicago, USA
• [Presentation] Role of fat (2013)
  • Author(s): Kohjiro Ueki
  • Organizer: World Diabetes Congress 2013
  • Place of Presentation: Melbourne Convention and Exhibition Centre, Melbourne, Australia
  • Invited
• [Presentation] ヒト脂肪組織発現解析を用いた病態特異的アディポカインの検索 (2013)
  • Author(s): 岡崎由希子、植木浩二郎、岩根亜弥、笹子敬洋、坂田道教、諏訪内浩紹、小林直樹、小林正稔、大杉 満、窪田直人、原一雄、山内敏正、吉村浩太郎、光嶋勲、油谷浩幸、門脇 孝
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: ホテル日航熊本、熊本
• [Presentation] 肥満症治療の課題と展望 (2013)
  • Author(s): 植木浩二郎
  • Organizer: 第63回日本体質医学会総会
  • Place of Presentation: 久留米大学筑水会館、久留米
  • Invited
• [Presentation] ヒト脂肪組織発現解析を用いた病態特異的アディポカインの検索 (2013)
  • Author(s): 岡崎由希子、岩根亜弥、笹子敬洋、坂田道教、諏訪内浩紹、小林正稔、原一雄、窪田直人、門脇孝、植木浩二郎
  • Organizer: 第34回日本肥満学会年次学術集会
  • Place of Presentation: 東京国際フォーラム、東京
• [Presentation] Identification of a novel adipokine involved in the development of obesity (2013)
  • Author(s): 岡崎由希子
  • Organizer: 第56回日本糖尿病学会年次学術集会
  • Place of Presentation: 熊本
• [Presentation] 2型糖尿病updateー成因と病態 (2012)
  • Author(s): 植木浩二郎
  • Organizer: 第85回日本内分泌学会総会
  • Place of Presentation: 名古屋
  • Invited
• [Presentation] 成因と病態に基づく 糖尿病治療を考える (2012)
  • Author(s): 植木浩二郎
  • Organizer: 第62回日本体質医学会総会
  • Place of Presentation: 大阪
  • Invited
• [Presentation] ヒト脂肪組織発現解析を用いた病態特異的アディポカインの検索 (2012)
  • Author(s): 岡崎由希子
  • Organizer: 第55回日本糖尿病学会年次学術集会
  • Place of Presentation: 横浜