Elucidation of pathophysiology and treatment strategies of peripheral clock disruption

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08550
• 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: Kanazawa University
• Principal Investigator: Ando Hitoshi 金沢大学, 医学系, 教授 (50382875)
• Co-Investigator(Kenkyū-buntansha): 藤原 浩 金沢大学, 医学系, 教授 (30252456) ; 大黒 多希子 金沢大学, 疾患モデル総合研究センター, 教授 (30767249)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 生活習慣病 / 生体リズム / 体内時計 / 時計遺伝子 / 肝 / GLP-1

Outline of Final Research Achievements

Accumulating evidence indicates that disruption of the circadian clock contributes to the development of lifestyle-related diseases. We have previously shown that exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, can strongly affect the molecular clocks. This study aimed to investigate the underlying mechanism and appropriate regimen of exenatide in mice. Exenatide administration at the beginning of the active period (i.e., in the morning for humans), but not at the beginning of the rest period, counteracted the phase shift effect of the rest period-restricted feeding. On the other hand, exenatide did not influence the phase of the hepatic clock under the active period-restricted feeding regardless of the dosing time. The effect of exenatide in wild-type mice weakened in central nervous system-specific GLP-1 receptor knockout mice. These findings may be useful in developing novel therapeutic strategies to prevent the onset and progression of lifestyle-related diseases.

Free Research Field

内分泌代謝学

Academic Significance and Societal Importance of the Research Achievements

本研究により、GLP-1受容体作動薬の体内時計を適切な時刻に投与することにより不規則な生活による体内時計障害を抑制できることが明らかになった。また、規則正しい生活をしている場合にはGLP-1受容体作動薬をいつ投与しても問題ないこと、GLP-1受容体作動薬は中枢神経を介して末梢臓器の体内時計を制御することも判明した。これらの成果はGLP-1受容体作動薬の治療効果の向上や新たな生活習慣病治療薬の開発につながる可能性があり、それらが実現した際の社会的意義は大きい。