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Inter-individual variations in circadian misalignment-induced NAFLD pathophysiology in mice
Nobuya Koike1, Yasuhiro Umemura1, Hitoshi Inokawa1,2
1Department of Physiology and Systems Bioscience, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
Abstract:
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.
Insights
Individual differences in how the body handles circadian misalignment, like from shift work, are linked to the robustness of internal body rhythms. This research used chronic jet-lag in mice to study these variations in liver disease development.
Area of Science:
- Chronobiology
- Metabolic Disease Research
- Animal Models
Background:
- Circadian misalignment, often due to shift work, causes varied health issues.
- Understanding individual differences in disease susceptibility is crucial for personalized prevention.
- Mechanisms underlying these variations in response to circadian disruption remain unclear.
Purpose of the Study:
- To investigate inter-individual differences in pre-symptomatic pathological progression following chronic jet-lag (CJL).
- To identify mechanistic links between circadian rhythm robustness and disease development.
- To explore potential predictive biomarkers for circadian rhythm disorders.
Main Methods:
- Utilized an integrative approach combining physiological, transcriptional, and histological phenotypes in wild-type mice.
- Exposed mice to chronic jet-lag (CJL) to model circadian misalignment.
- Analyzed hepatic transcriptomic signatures and histopathological changes, correlating them with behavioral rhythm characteristics.
Main Results:
- CJL significantly increased hepatic steatosis prevalence with marked inter-individual variability.
- Transcriptomic analysis revealed dysregulation of lipid metabolism pathways in affected mice.
- The robustness (period and power) of intrinsic behavioral rhythms correlated with CJL-induced gene expression patterns.
Conclusions:
- Circadian rhythm robustness influences individual susceptibility to diseases caused by circadian misalignment.
- Dysregulation of lipid metabolism is a key factor in CJL-induced liver pathology.
- Rhythm characteristics may serve as predictive indicators for circadian rhythm disorders and related diseases.
