Koike Nobuya, Umemura Yasuhiro, Inokawa Hitoshi, Tokuda Isao, Tsuchiya Yoshiki, Sasawaki Yuh, Umemura Atsushi, Masuzawa Naoko, Yabumoto Kazuya, Seya Takashi, Sugimoto Akira, Yoo Seung-Hee, Chen Zheng, Yagita Kazuhiro
Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
Department of Human Nutrition, Chugoku Gakuen University, Okayama 701-0197, Japan.
iScience. 2024 Feb 5;27(2):108934. doi: 10.1016/j.isci.2024.108934. eCollection 2024 Feb 16.
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 pre-symptomatic pathological progression, preceding irreversible disease onset, in 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 were found to significantly correlate with CJL-induced gene signatures. Together, our results suggest circadian rhythm robustness of the animals contributes to inter-individual variations in pathogenesis of circadian misalignment-induced diseases and raise the possibility that these physiological indicators may be available for predictive hallmarks of circadian rhythm disorders.
昼夜节律失调的病理后果，如轮班工作，存在相当大的个体差异，但由于缺乏对其机制的了解，阻碍了预防和减轻疾病症状的精准预防。在这里，我们采用了一种综合方法，涉及生理、转录和组织学表型，以研究在暴露于慢性时差反应（CJL）的野生型小鼠中，在不可逆疾病发作之前的症状前病理进展中的个体差异。我们观察到，CJL显著增加了肝脂肪变性的患病率，且个体差异明显。通过组织病理学分析验证，根据CJL诱导的肝脏转录组特征对个体小鼠进行分层，确定了脂质代谢的失调。此外，发现内在行为节律的周期和强度与CJL诱导的基因特征显著相关。总之，我们的结果表明，动物的昼夜节律稳健性导致了昼夜节律失调相关疾病发病机制中的个体差异，并增加了这些生理指标可能成为昼夜节律紊乱预测标志的可能性。
