Internal desynchrony of the circadian clock system in middle-aged mice under social jet lag-like conditions

Social jet lag (SJL) refers to the discrepancy in sleep patterns between weekdays and weekends, leading to a misalignment between the internal clock and social time. In this study, we investigated the effects of weekly shifts in light-dark (LD) conditions: two days per week with 6-h delayed LD cycles (simulating Saturday and Sunday), followed by a 6-h advance on Monday. Core body temperature rhythms rapidly entrained to the delayed LD cycles on weekends, and these delayed rhythms persisted even after the LD cycle was advanced on Monday. In contrast, plasma corticosterone rhythms on Mondays were aligned with the LD cycle but exhibited reduced amplitude. In the livers of SJL mice on Monday, the expression rhythms of Per1, Per2, and Hsp70 were delayed by 3-5 h compared to that in the controls, whereas Rev-erb expression rhythms remained comparable to those of the controls. The expression of lipid and glucose metabolism-related genes in the liver showed either delayed rhythms or no significant changes. To determine whether the dissociation of gene expression rhythms resulted from gene-specific responses to circadian body temperature and hormonal signals, we conducted ex vivo culture experiments using mouse liver slices. High-temperature stimulation induced Per2 and Hsp70 expression, while dexamethasone induced Per1 expression. High temperature and dexamethasone affected distinct sets of metabolic genes, whereas insulin induced only minor changes. Moreover, these responses were strongly influenced by the age and light exposure of the mice. We also examined the effect of weekly housing by providing environmental enrichment (EE), which had minimal impact on circadian parameters but promoted anti-aging effects on bone density and behavior. Overall, our findings indicate that weekly shifts in LD cycles induce internal desynchronization within the hepatic molecular clock and metabolic pathways by uncoupling core body temperature rhythms, hormonal rhythms, and gene-specific responses to stimuli.