Abstract

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. Description Female mice are more resilient to circadian misalignment than males, and this sexual dimorphism is conserved in human shift workers. Cardiometabolic sex differences in circadian stress Working night shifts increases risk of cardiometabolic dysfunction. Anderson et al. report that among mice on a high-fat diet and an altered circadian schedule similar to that of shiftwork, females were more resilient to the cardiometabolic consequences of the regimen compared with male mice, which showed stress-related changes at both the tissue and microbiome levels. Sexual dimorphism in cardiometabolic dysfunction was replicated in a human cohort of shiftworkers and might in part explain why males are more prone to developing metabolic disease. —Catherine A. Charneski