Genetic synchronization of the brain and liver molecular clocks defend chrono- metabolic disease

• 成果类型: Article
• 署名作者: Woodie, Lauren N.; Alberto, Ahren J.; Krusen, Brianna M.; Melink, Lily C.; Lazar, Mitchell A.
• 署名单位: University of Pennsylvania
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9260
• DOI: 10.1073/pnas.2417678121
• 发表日期: 2024-12-09
• 关键词: insulin-resistance; circadian clocks; disruption; endocrine; deficient; component; obesity; alpha; leads; mice

摘要

Nearly every cell of the body contains a circadian clock mechanism that is synchronized with the light- entrained clock in the suprachiasmatic nucleus (SCN). Desynchrony between the SCN and the external environment leads to metabolic dysfunction in shift workers. Similarly, mice with markedly shortened endogenous period due to the deletion of circadian REV- ERB alpha/beta nuclear receptors in the SCN (SCN DKO) exhibit increased sensitivity to diet- induced obesity (DIO) on a 24 h light:dark cycle while mice with REV-ERBs deleted in hepatocytes (HepDKO) display exacerbated hepatosteatosis in response to a high- fat diet. Here, we show that inducing deletion of hepatocyte REV-ERBs in SCN DKO mice (Hep-SCN DDKO) rescued the exacerbated DIO and hepatic triglyceride accumulation, without affecting the shortened behavioral period. These findings suggest that metabolic disturbances due to environmental desynchrony with the central clock are due to effects on peripheral clocks which can be mitigated by matching peripheral and central clock periods even in a desynchronous environment. Thus, maintaining synchrony within an organism, rather than between endogenous and exogenous clocks, may be a viable target for the treatment of metabolic disorders associated with circadian disruption.