| Project/Area Number |
18K08503
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 54040:Metabolism and endocrinology-related
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| Research Institution | Juntendo University (2020)
The University of Tokyo (2018-2019) |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
笹子 敬洋 東京大学, 医学部附属病院, 助教 (20550429)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| 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)
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| Keywords | Activin B / FSTL3 / 糖新生 / FGF21 / Activin / アクチビン |
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| 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.
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| 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。
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