Endocannabinoid signaling is a critical link between circadian desynchronization and metabolic dysfunction

Area of Science:

• Metabolic research
• Chronobiology
• Endocrinology

Background:

• Circadian rhythm disruption is linked to metabolic dysregulation.
• The specific mechanisms underlying this link are not fully understood.
• The endocannabinoid system's role in circadian disruption effects is unexplored.

Purpose of the Study:

• To investigate the role of cannabinoid receptor 1 (CB1r) in mediating the metabolic effects of environmental circadian desynchronization (ECD).
• To elucidate the specific tissues and mechanisms involved in ECD-induced metabolic dysfunction.

Main Methods:

• Utilized wild-type (WT) and CB1r knockout (KO) mouse models, including liver-specific CB1r KO mice.
• Measured endocannabinoid levels (AEA, 2-AG) in plasma and liver.
• Assessed metabolic, behavioral, and physiological responses to ECD.
• Analyzed gene expression related to oxidative phosphorylation in the liver.

Main Results:

• ECD increased AEA and 2-AG levels in plasma and liver.
• Global CB1r KO protected against metabolic effects of ECD, despite similar behavioral/physiological responses.
• Liver-specific CB1r KO demonstrated that liver CB1r mediates ECD-induced metabolic hormone disruption, but not weight gain.
• ECD upregulated oxidative phosphorylation gene transcription in WT mouse livers, but not in liver-specific CB1r KO mice.

Conclusions:

• Metabolic dysfunction caused by ECD is dependent on cannabinoid receptor 1 (CB1r) signaling.
• Liver CB1r plays a crucial role in mediating metabolic hormone dysregulation and altered gene expression in response to circadian disruption.
• ECD induces tissue-specific metabolic alterations through CB1r signaling, with the liver being a key organ involved.