Contribution of adipocytes on regulating bile acid metabolism in liver and glucose homeostasis

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K00846
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Eating habits
• Research Institution: Chiba University
• Principal Investigator: LEE Eun Young 千葉大学, 大学院医学研究院, 助教 (60583424)
• Co-Investigator(Kenkyū-buntansha): 三木 隆司 千葉大学, 大学院医学研究院, 教授 (50302568)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: 糖新生 / 脂肪移植 / 胆汁酸

Outline of Final Research Achievements

Recent increase of the patients with diabetes mellitus is partly attributable to excessive fat intake. However, its pathogenesis remained unclarified due to the lack of good animal models. We previously found that insulin receptor mutant mice (mIR mice) develop hyperglycemia under high fat diet (HFD). Interestingly, hyperglycemia of these mice (mIR/HFD) was significantly attenuated by fat transplantation. We also found that fat transplantation ameliorated increased gluconeogenesis and increased hepatic expression of Cyp7a1, the rate limiting enzyme for bile acid synthesis. A subset of bile acids, including bile acid B, was increased in the plasma by fat transplantation. Administration of bile acid B to mIR/HFD significantly suppressed hyperglycemia associated with the increase in the expression of Hmgcoar, the rate limiting enzyme for cholesterol synthesis in the liver. Our data suggested that adipose tissue impacts glucose metabolism by modulating bile acid metabolism in the liver.

Free Research Field

糖尿病

Academic Significance and Societal Importance of the Research Achievements

脂肪感受性糖尿病モデルマウスであるmIR/HFDマウスの解析から、脂肪組織のインスリン抵抗性が胆汁酸代謝異常を介して、糖代謝の破綻に寄与していることが明らかになった。この結果により、脂肪組織のインスリン抵抗性解除が、胆汁酸代謝を介して、糖尿病を改善させる新たな分子機序が示され、大きな学術的意義を有している。また、脂肪移植により増加した胆汁酸BをmIR/HFDへ投与することにより、肝臓の糖新生を抑制され血糖が改善した。同様の効果がヒト糖尿病患者でも見られることが考えられ、胆汁酸Bは新たな糖尿病治療薬として有効である可能性が考えられた。