Sex-dependent Effects of Chronic Jet Lag on Circadian Rhythm and Metabolism in Mice

Background: The circadian clock integrates external environmental changes into the internal physiology of organisms. Perturbed circadian clocks due to misaligned light cycles increase the risk of diseases, including metabolic disorders. However, the effects of sex differences in this context remain unclear.

Methods: Circadian misalignment was induced by a chronic jet lag (CJL) shift schedule (light-on time advanced by 6 h every 2 days) in C57BL/6N male and female mice. Core body temperature and activity rhythms were recorded using a nano tag, and the gene expression rhythms of clock and clock-controlled genes in the liver and adrenal glands were analyzed using qPCR. Glucose metabolism and insulin response were evaluated using glucose tolerance, insulin sensitivity, and glucose response assays. Castration and testosterone replacement were performed to assess the fundamental role of testosterone in male phenotypes under CJL.

Results: Under CJL treatment, male mice exhibited increased weight gain, whereas females exhibited decreased weight gain compared to that of the respective controls. CJL treatment induced a lower robustness of circadian rhythms in core body temperature and a weaker rhythm of clock gene expression in the liver and adrenal glands in females, but not in males. Only male mice exhibited glucose intolerance under CJL conditions, without the development of insulin resistance. Castrated mice without testosterone exhibited decreased weight gain and reduced robustness of body temperature rhythm, as observed in intact females. Testosterone replacement in castrated mice recovered the CJL-induced weight gain, robustness of temperature rhythm, and glucose intolerance observed in intact males.

Conclusions: Significant sex-based differences were observed in circadian clock organization and metabolism under CJL. Testosterone plays a crucial role in maintaining the circadian clock and regulating CJL metabolism in males.