睡眠時無呼吸症候群モデルにおける慢性間欠的低酸素症が概日代謝構造に及ぼす再形成

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.