The mechanism of obesity formation by loss of function of the clock gene BMAL1

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07020
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
• Research Institution: Nihon University
• Principal Investigator: SHIMBA Shigeki 日本大学, 薬学部, 教授 (20287668)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 体内時計 / 肥満 / Bmal1

Outline of Final Research Achievements

Purpose: Disruption of the circadian clock induces obesity. In this study, we analyzed the mechanism by which impaired circadian rhythm function in the mice adipose tissue induces obesity using the adipose tissue-specific Bmal1knockout mice. Results: Brown adipocyte-specific Bmal1 deficiency resulted in reduced energy expenditure and obesity in mice. Furthermore, mice lacking Bmal1 in the white adipose tissue showed an increase in insulin sensitivity, resulting in hypertrophy of adipocytes. The respiratory quotient of the white adipose tissue-specific Bmal1 KO mice lacked circadian rhythm
and was high throughout the day. In addition, a decrease in the amount of free fatty acids in the blood was observed during the resting period. Conclusion: These results indicate that a decrease in the level of BMAL1, i.e., impaired circadian clock function, induces obesity by decreasing heat production and increasing insulin sensitivity.

Free Research Field

代謝学

Academic Significance and Societal Importance of the Research Achievements

脂肪細胞は、従来、単に中性脂肪を蓄積する受け身の細胞として認識されてきたが、肥満遺伝子の産物であるレプチンの発見以来、内分泌細胞として積極的にエネルギー代謝調節に重要な役割を果たすこと、そしてその機能低下により様々な疾病が発症することが明らかにされてきた。したがって、本研究は、単に脂肪細胞機能の調節におけるBMAL1の新たな役割を解明するにとどまらず、脂肪細胞の機能変化に起因した疾病の発症並びにその時間薬物治療の分子基盤、さらにはメタボリックシンドロームの一次予防を目指した「規則正しい生活の励行」に科学的エビデンスを与えるものである。