Chronic intermittent hypoxia reshapes circadian metabolic architecture in a model of sleep apnea.

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 chronic hypoxia. Through integrated circadian transcriptomic, metabolomic, and physiological 24-hour profiling, we show that 4 weeks of rest phase-restricted IH reprograms hepatic and systemic 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 toward oxygen-sparing processes such as gluconeogenesis, glycogen turnover, and lipid mobilization. These changes align with the hypoxic phase exposure and coincide with reshaped hepatic metabolite oscillations and systemic autonomic rhythms, supporting a functional adaptation to intermittent oxygen availability. Mechanistically, we identify the cAMP-CREB1 pathway as a driver of circadian transcriptional remodeling in the liver and a central integrator of IH-dependent adrenergic stress. Our findings establish chronic IH as a potent metabolic zeitgeber that rewires hepatic transcriptional and metabolic programs, revealing a circadian dimension to the metabolic consequences of sleep-disordered breathing.