Elucidation of inter-organ insulin-leptin signal crosstalk originating in the liver

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08522
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Tohoku University
• Principal Investigator: Takahashi Kei 東北大学, 医学系研究科, 助教 (00644808)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: インスリン作用

Outline of Final Research Achievements

In inducible liver insulin receptor knockout mice, body weights are increased with hyperphagia and decreased energy expenditure, accompanied by increased circulating leptin receptor (LepR) and decreased hypothalamic leptin actions. Additional hepatic LepR deficiency reverses these metabolic phenotypes. Thus, decreased hepatic insulin action suppresses hypothalamic leptin action with increased liver-derived soluble LepR. Human hepatic and circulating LepR levels also correlate negatively with hepatic insulin action indices. In mice, food restriction decreases hepatic insulin action and energy expenditure with increased circulating LepR. Hepatic LepR deficiency increases mortality with enhanced energy expenditure during food restriction. Collectively, the liver translates metabolic cues regarding energy-deficient status, which is reflected by decreased hepatic insulin action, into soluble LepR, thereby suppressing energy dissipation and assuring survival under food shortages.

Free Research Field

糖尿病

Academic Significance and Societal Importance of the Research Achievements

興味深いことに、ヒトサンプルにおいても肝インスリン作用低下を反映する所見とsLepRとに相関がみられ、本機構はヒトにおいても機能することが示唆された。また、食物不足の状況を再現した実験を通じ、肝は食物不足の状況を肝インスリン作用低下を介して覚知し、その代謝情報をsLepRへと変換することでレプチン作用を抑制し、エネルギー消費を抑えて生存を後押しすることが明らかとなった。以上から、本研究により生物が生きる仕組み（生存戦略）の理解を書き換え、代謝性疾患の新規治療開発にも貢献した。