Mechanism of transcriptional regulation via skeletal muscle glucocorticoid receptor

2016 Fiscal Year Final Research Report

• Project/Area Number: 26461375
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Endocrinology
• Research Institution: The University of Tokyo
• Principal Investigator: SHIMIZU NORIAKI 東京大学, 医科学研究所, 特任講師 (30396890)
• Co-Investigator(Renkei-kenkyūsha): TANAKA Hirotoshi 東京大学, 医科学研究所, 教授 (00171794)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: メカノバイオロジー / 核内受容体 / ミオパチー / アトロジーン / FGF21 / 肥満 / 脂質代謝 / ステロイド

Outline of Final Research Achievements

Skeletal muscle has a pleiotropic role in organismal energy metabolism, for example, by storing protein as an energy source, or by excreting endocrine hormones. Muscle proteolysis is tightly controlled by a glucocorticoid-driven transcriptional programme. We unraveled the physiological significance of this catabolic process using skeletal muscle-specific glucocorticoid receptor (GR) knockout (GRmKO) mice. These mice have increased muscle mass but smaller adipose tissues. GRmKO mice show a drastic shift of energy utilization and storage in muscle, liver and adipose tissues. We demonstrate that the resulting depletion of plasma alanine serves as a cue to increase plasma levels of fibroblast growth factor 21 (FGF21) and activates liver-fat communication, leading to the activation of lipolytic genes in adipose tissues. We propose that this muscle-liver-adipose signaling axis may serve as a target for the development of therapies against various metabolic diseases, including obesity.

Free Research Field

内分泌学