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

🥉 Top 5% JournalOct 17, 2025Molecular metabolism

Sex differences in how liver cell clock protein Period 1 affects time-restricted feeding

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Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Time-restricted feeding (TRF) significantly reduced weight gain and improved metabolic parameters in male mice lacking the hepatocyte gene Period 1 (Per1).

TRF decreased weight gain and lipid accumulation in male mice without Per1 when compared to ad libitum feeding.
In female mice, the absence of hepatocyte Per1 did not lead to significant improvements in weight gain or glucose tolerance with TRF.
TRF enhanced energy expenditure and lipid metabolism in males with Per1, but these effects were sex-dependent.
Gene expression analysis showed that lipid metabolism genes were differentially regulated in response to TRF based on the presence of Per1 in females.

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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 (Per1and Per1) were subjected to either ad libitum feeding (ALF) or TRF restricted to the active phase (8 h/day). fl/fl LKO

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 Per1and Per1males. 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 Per1and Per1female mice. fl/fl LKO fl/fl LKO

CONCLUSIONS: Hepatocyte Per1 mediates the energy, lipid, and glucose homeostatic effects of TRF, and this regulation is almost completely sex-dependent.

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