Sexual dimorphism in the response to chronic circadian misalignment

Longitudinal studies associate shiftwork with cardiometabolic disorders but do not establish causation nor elucidate mechanisms of disease. We developed a mouse model based on shiftwork schedules to study circadian misalignment in both sexes, where misaligned mice undergo an 8-hour phase advance every week for 15 weeks. Behavioral and transcriptional rhythmicity were preserved in female mice despite exposure to misalignment. Females were protected against the cardiometabolic impact of circadian disruption 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. In the UK biobank, female shiftworkers showed stronger circadian rhythmicity in activity and a lower incidence of metabolic syndrome than males. Thus we show that female mice are resilient to chronic circadian misalignment, and that these differences are conserved in humans.