Circadian disruption impairs glucose homeostasis in male but not in female mice and is dependent on gonadal sex hormones

Abstract

Circadian disruption (CD) is the consequence of a mismatch between endogenous circadian rhythms and behavior, and frequently occurs in shift workers. CD has often been linked to impairment of glucose and lipid homeostasis. It is, however, unknown if these effects are sex dependent. Here, we subjected male and female C57BL/6J mice to 6-h light phase advancements every 3 days to induce CD and assessed glucose and lipid homeostasis. Within this model, we studied the involvement of gonadal sex hormones by injecting mice with gonadotropin-releasing hormone-antagonist degarelix. We demonstrate that CD has sex-specific effects on glucose homeostasis, as CD elevated fasting insulin levels in male mice while increasing fasting glucose levels in female mice, which appeared to be independent of behavior, food intake, and energy expenditure. Absence of gonadal sex hormones lowered plasma insulin levels in male mice subjected to CD while it delayed glucose clearance in female mice subjected to CD. CD elevated plasma triglyceride (TG) levels and delayed plasma clearance of TG-rich lipoproteins in both sexes, coinciding with reduced TG-derived FA uptake by adipose tissues. Absence of gonadal sex hormones did not notably alter the effects of CD on lipid metabolism. We conclude that CD causes sex-dependent effects on glucose metabolism, as aggravated by male gonadal sex hormones and partly rescued by female gonadal sex hormones. Future studies on CD should consider the inclusion of both sexes, which may eventually contribute to personalized advice for shift workers.

Keywords: circadian disruption; glucose homeostasis; gonadal hormones; lipid homeostasis; sex.