Sexual dimorphism in the response to chronic circadian misalignment on a high-fat diet

Longitudinal studies associate shiftwork with cardiometabolic disorders but do not establish causation or elucidate mechanisms of disease. We developed a mouse model based on shiftwork schedules to study circadian misalignment in both sexes. Behavioral and transcriptional rhythmicity were preserved in female mice despite exposure to misalignment. Females were protected from the cardiometabolic impact of circadian misalignment on a high-fat diet seen in males. The liver transcriptome and proteome revealed discordant pathway perturbations between the sexes. Tissue-level changes were accompanied by gut microbiome dysbiosis only in male mice, biasing toward increased potential for diabetogenic branched chain amino acid production. Antibiotic ablation of the gut microbiota diminished the impact of misalignment. In the United Kingdom Biobank, females showed stronger circadian rhythmicity in activity and a lower incidence of metabolic syndrome than males among job-matched shiftworkers. Thus, we show that female mice are more resilient than males to chronic circadian misalignment and that these differences are conserved in humans.

Automated summary

Longitudinal studies suggest a relationship between shiftwork and cardiometabolic disorders, but the causes and mechanisms are not clear. We developed a mouse model to study circadian misalignment in both sexes and found that female mice showed preserved rhythmicity and were protected from the cardiometabolic effects of misalignment on a high-fat diet. Differences were observed in the liver transcriptome and proteome, as well as gut microbiome dysbiosis, which only occurred in male mice. Antibiotic treatment reduced the impact of misalignment. In the UK Biobank, female shiftworkers demonstrated stronger circadian rhythmicity and a lower incidence of metabolic syndrome compared to males. Our findings suggest that females are more resilient to chronic circadian misalignment, and this difference is conserved in humans.