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. 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.

昼夜节律紊乱（如轮班工作）所引发的病理结局存在显著的个体差异，但目前对其机制的认知不足，阻碍了精准预防以阻断或减轻疾病症状。本研究针对暴露于慢性时差（chronic jet-lag, CJL）环境的野生型小鼠，采用整合了生理、转录组与组织表型的研究策略，旨在探究慢性昼夜节律紊乱引发不可逆疾病前的症状前期阶段中，病理进展的个体差异。本研究观察到，慢性时差处理显著提升了肝脂肪变的患病率，且该效应存在显著的个体差异。通过组织病理学分析验证后，基于慢性时差诱导的肝脏转录组特征对个体小鼠进行分层，可精准定位脂质代谢失调这一核心异常。此外，本研究发现小鼠内在行为节律的周期与振幅，与慢性时差诱导的基因表达特征存在显著相关性。综上，本研究结果表明，动物的昼夜节律稳定性是导致昼夜节律紊乱相关疾病发病机制存在个体差异的重要因素，同时提示上述生理指标有望作为昼夜节律紊乱的预测性标志物。本研究还对暴露于慢性昼夜节律紊乱环境及正常对照环境的小鼠肝脏中的poly(A)+富集RNA进行了检测。实验对象为雄性野生型C57BL/6J小鼠，实验组采用每4天向前8小时的慢性时差处理（简称ADV范式），持续47周；对照组（LD组）则维持标准12小时光照:12小时黑暗的正常光周期环境。