Dimorphic regulation of time-restricted feeding effects by hepatocyte Period 1

Abstract

Objectives: Obesity is linked to metabolic disorders including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease, and cardiovascular disease. Lifestyle interventions, such as time-restricted feeding (TRF), have proven to be effective for long-term weight management. The metabolic effects of TRF are closely associated with circadian clock function in the liver. We previously demonstrated that the circadian gene Period 1 (Per1) mediates responses to acute fasting in both sexes. We therefore hypothesized that hepatocyte Per1 contributes to the long-term adaptations to repeated fasting exposure in the form of TRF, and investigated its role in diet-induced obesity in both sexes. Methods: Male and female mice with or without hepatocyte Per1 (Per1fl/fl and Per1LKO) were subjected to either ad libitum feeding (ALF) or TRF restricted to the active phase (8 h/day). Results: TRF attenuated Western diet-induced weight gain and peripheral and hepatic lipid accumulation, and improved heat production, metabolic substrate flexibility, and glucose homeostasis in Per1fl/fl and Per1LKO males. In contrast, hepatocyte Per1 was required for TRF-induced improvements in energy expenditure and peripheral and hepatic lipid accumulation in females. Surprisingly, TRF failed to significantly attenuate diet-induced weight gain or glucose and insulin tolerance in females independent of genotype. Transcriptomic data revealed sex-specific transcriptional responses to TRF and to hepatocyte-specific Per1 deletion. Specifically, genes involved in lipid metabolism were differentially regulated when comparing TRF-treated Per1fl/fl and Per1LKO female mice. Conclusions: Hepatocyte Per1 mediates the energy, lipid, and glucose homeostatic effects of TRF, and this regulation is almost completely sex-dependent.