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

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 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE245519 | GEO | 2024/04/03

REPOSITORIES: GEO

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Project description:Sleep has been strongly implicated in learning and especially in the reprocessing of recently acquired memory. Children with intellectual disability (ID) tend to have sleep-wake disturbances, which may contribute to the pathophysiology of the disease. As far as sleep is, in part, a circadian process, we decided to study rhythmic gene expression in hippocampus, a brain structure, which plays a key role in memory in human and rodents. By investigating the transcriptome of mouse adult hippocampus, we report here the identification of 663 circadian rhythm (CR)-regulated genes, which have been clustered in four categories, based on their temporal pattern of expression. In addition to the standard core-clock genes, enrichment analysis of the hippocampal CR-regulated genes revealed the presence of several transcription factors, underlying the existence of an inter-regulation of genes' expression between clusters. Interestingly, these hippocampal circadian rhythm-regulated genes are very enriched in sleep/wakefulness related genes. We show here that glucocorticoid signaling, already shown to be involved in memory regulation, is a circadian regulated pathway in hippocampus. Furthermore, we identified a list of 30 CR-regulated ID genes. Our results demonstrate that hippocampus can be considered as a peripheral oscillator and illustrate the link between circadian rhythm, sleep, intellectual disability and memory consolidation. In order to identify circadian rhythm-regulated genes in mouse hippocampus, we realized a study in dark-dark conditions, thus allowing to overcome the effects induced by light changes. To systematically identify genes with circadian regulated expression, RNA samples from the hippocampus of three mice at four Circadian Time (CT) points were used for expression profiling using Agilent microarray technology. The dark/dark period started at 7 p.m. The Circadian Time (CT) 18 samples were taken after 30 h of continuous dark; the other circadian times followed at 6-h intervals: CT0, CT6 and CT12 after 36, 42 and 48 h of continuous darkness, respectively.

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

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