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Chronic intermittent hypoxia mimicking sleep apnea reshapes the liver circadian metabolic architecture

ABSTRACT: Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (IH) during sleep, is increasingly recognized as a driver of metabolic dysfunction. However, its impact on circadian metabolic regulation remains poorly understood. Here, we investigated how chronic IH reshapes 24- hour hepatic and systemic metabolic programs in a mouse model mimicking OSA-associated hypoxia. Through integrated circadian transcriptomic, metabolomic, and physiological profiling, we show that four weeks of rest phase-restricted IH reprogram hepatic metabolism in a time-specific manner. This reorganization involves the coordinated circadian regulation of glucose, lipid, and redox pathways, with a shift away from oxidative metabolism and toward oxygen-sparing processes such as gluconeogenesis, glycogen turnover, and lipid mobilization. These changes align with the hypoxic phase and coincide with altered metabolite oscillations and autonomic rhythms, supporting a functional adaptation to intermittent oxygen availability. Mechanistically, we identify rhythmic activation of the cAMP–CREB1 axis as a key transcriptional driver linking adrenergic signaling to circadian metabolic remodeling under IH. Our findings establish chronic IH as a potent metabolic zeitgeber that entrains hepatic transcriptional and metabolic rhythms, revealing a circadian dimension to the metabolic consequences of sleep-disordered breathing.

ORGANISM(S): Mus musculus

PROVIDER: GSE302604 | GEO | 2026/01/16

REPOSITORIES: GEO

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Project description:BACKGROUND: Epigenetic processes enable the environment to modulate gene transcription during fetal development, ultimately leading to stable phenotypic changes throughout the lifespan. There is a relatively high prevalence of altered sleep patterns during late gestation, especially obstructive sleep apnea (OSA). Intermittent hypoxia (IH) is a hallmark of OSA caused by periodic obstructions of the upper airway, which occurs along with sleep fragmentation (SF). We have previously shown that adult offspring of late gestational SF (LG-SF) mothers exhibited metabolic alterations via epigenomic alterations. The aims of this study were to investigate the effects of LG-IH on metabolic features in offspring and to determine the effects of LG-IH on the epigenome of visceral white adipose tissue (VWAT) in the offspring. METHODS: Time-pregnant mice were exposed to LG-IH or room air (RA) paradigms conditions during the last 6 days of gestation (LG-IH and LG-RA groups, respectively). Offspring were weaned at 21 days and fed with normal chow diet. At 24 weeks, lipid profiles and metabolic parameters were assessed. We performed large scale DNA methylation analysis using MeDIP coupled to microarrays (MeDIP-chip) in offspring VWAT (n=8 mice per group). Regions exhibiting differential DNA methylation (DMRs) between the groups were mapped to their corresponding genes and tested for potential overlaps with biological processes and pathways using Ingenuity Pathway Analysis. RESULTS: We detected 1520 DMRs between the LG-IH and LG-RA groups (p< 0.0001, two-way ANOVA), associated with 693 genes. A significant portion of these genes (n=162) were also associated with previously identified DMRs in LG-SF offspring (p=1.35 x 10-97, hypergeometric test). Pathway analyses showed that genes affected by LG-IH and LG-SF, were mainly associated with molecular processes related to metabolic regulation and inflammatory response. In particular for LG-IH, biochemical pathways related to energy production through amino acid and fatty acid metabolism (i.e. methionine, choline and 2-oxobutanoate degradation pathways, methylmalonyl pathway, cysteine biosynthesis, etc.). CONCLUSIONS: Our findings suggest a major role for epigenomic alterations in the metabolic dysfunction of adult offspring born to LG-IH and LH-SF mothers. Furthermore, whereas LG-IH may concomitantly act upon metabolic pathways also affected by LG-SF, LG-IH also affects biochemical processes underlying energy production in VWAT of the offspring.

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Chronic intermittent hypoxia mimicking sleep apnea reshapes the liver circadian metabolic architecture

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