Inter-individual variations in circadian misalignment-induced NAFLD pathophysiology in mice

Pathological consequences of circadian misalignment, such as shift work, show considerable individual differences, but the lack of mechanistic understanding hinders precision prevention to prevent and mitigate disease symptoms. Here, we employed an integrative approach involving physiological, transcriptional, and histological phenotypes to examine inter-individual differences in pathological progression during the pre-symptomatic stage, prior to the development of irreversible diseases under chronic circadian misalignment, using wild-type mice exposed to chronic jet-lag (CJL). We observed that CJL markedly increased the prevalence of hepatic steatosis with pronounced inter-individual differences. Stratification of individual mice based on CJL-induced hepatic transcriptomic signature, validated by histopathological analysis, pinpoints dysregulation of lipid metabolism. Moreover, the period and power of intrinsic behavioral rhythms was found to significantly correlate with CJL-induced gene signatures. Together, our results suggest circadian rhythm robustness of the animals contribute to inter-individual variations in pathogenesis of circadian misalignment-induced diseases, and arise the possibility that these physiological indicators may be available for predictive hallmarks of circadian rhythm disorders. Overall design: Examination of poly(A)+ enriched RNAs in mouse liver exposed to chronic circadian misalignment in addition to control. Wild-type male C57BL/6J mice were exposed to chronic jet lag characterized by 8-hour advance every 4 days (referred to as ADV paradigm) for 47 weeks, whereas the control group (LD) were maintained under the normal 12h:12h light-dark condition.