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Elucidation of the mechanism of glucose metabolism regulation by Activin

Research Project

Project/Area Number 18K08503
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 54040:Metabolism and endocrinology-related
Research InstitutionJuntendo University (2020)
The University of Tokyo (2018-2019)

Principal Investigator

Okazaki Yukiko  順天堂大学, 医学部, 准教授 (30422299)

Co-Investigator(Kenkyū-buntansha) 笹子 敬洋  東京大学, 医学部附属病院, 助教 (20550429)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
KeywordsActivin B / FSTL3 / 糖新生 / FGF21 / Activin / アクチビン
Outline of Final Research Achievements

We have analyzed the expression profiles in adipose tissues of human subjects who were taken in the surgery. We found that the expression of FSL3 is increased in accordance with increasing BMI in visceral and subcutaneous fat of human subjects. FSTL3 is known to bind to Activin B, thereby inhibiting its function. In glucose tolerance test, mice overexpressing ActivinB exhibited significantly lower glucose levels. In insulin tolerance tests, these mice showed significantly improved insulin sensitivity.
We found that Activin B has the glucose lowing effect by suppressing gluconeogenesis via the ALK2-dependent signaling pathway. We also found that Activin B has the glucose lowing effect by inducing the expression of FGF21 via the ALK4-Smad2 signaling pathway. In the obese state, increased FSTL3 antagonizes Activin B, thereby causing hyperglycemia or Diabetes mellitus. Enhancing the action of Activin B can be a novel therapeutic strategy for the treatment of diabetes.

Academic Significance and Societal Importance of the Research Achievements

肥満に伴う糖尿病患者が世界中で急増し大きな問題になっている。この病態解明と治療開発のためには、ヒトの脂肪組織を用いた研究が重要であると考え、日本人の脂肪組織を検討し、その結果、FSTL3(Follistatin like-3)の発現がごく初期の肥満段階から有意に上昇することが分かった(ドイツ人の脂肪組織でも同じ結果であることを確認した)。
FSTL3は「強力な血糖降下作用を有するActivin B」の作用を阻害することを我々は見いだし、Activin Bの血糖降下作用のメカニズムには少なくとも2つの経路があることを示した。Activin Bは糖尿病の新規治療薬として有力な候補と考えられる。

Report

(3 results)
  • 2020 Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (6 results)

All 2019 2018

All Presentation (6 results) (of which Int'l Joint Research: 1 results)

  • [Presentation] Activin B-Fstl3による代謝制御機構とその破綻による代謝異常2019

    • Author(s)
      Naoki Kobayashi, Yukiko Okazaki, Takashi Kadowaki, Kohjiro Ueki
    • Organizer
      Cardio Renal Diabetes Conference 2019
    • Related Report
      2018 Research-status Report
  • [Presentation] Activin B-Fstl3による代謝制御機構とその破綻による代謝異常2019

    • Author(s)
      小林直樹、岡崎由希子、門脇孝、植木浩二郎
    • Organizer
      第33回 糖尿病・肥満動物学会 年次学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] Activin/FSTL3による糖代謝制御機構2018

    • Author(s)
      岡崎由希子、小林直樹、岩根亜弥、笹子敬洋、諏訪内浩紹、小林正稔、窪田直人、山内敏正、門脇 孝、植木浩二郎
    • Organizer
      第39回日本肥満学会
    • Related Report
      2018 Research-status Report
  • [Presentation] Activin B - Fstl3による代謝制御機構とその破綻による代謝異常2018

    • Author(s)
      小林直樹、岡崎由希子、門脇孝、植木浩二郎
    • Organizer
      第61回 日本糖尿病学会年次学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] Hepatic Activin B controls glucose metabolism2018

    • Author(s)
      Naoki Kobayashi, Yukiko Okazaki, Takashi Kadowaki, Kohjiro Ueki
    • Organizer
      39th JASSO, APDO SYMPOSIUM 2018 Asia-Pacific Diabetes and Obesity Study Group Joint with the 39th Annual Meeting of Japan Society for the Study of Obesity
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Activin B-Fstl3による代謝制御機構とその破綻による代謝異常2018

    • Author(s)
      小林直樹、岡崎由希子、門脇孝、植木浩二郎
    • Organizer
      第33回 日本糖尿病合併症学会
    • Related Report
      2018 Research-status Report

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Published: 2018-04-23   Modified: 2022-01-27  

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