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

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. Overall design: Male C57BL/6JRj mice were exposed to chronic intermittent hypoxia (60 cycles h-¹, 5 % FiO2, ZT0 – ZT8) or normoxic air for four weeks. Livers were collected every 4 h over a 24-h cycle (ZT0, 4, 8, 12, 16, 20) and poly-A-selected, strand-specific RNA-seq libraries were prepared and sequenced (2 × 100 bp, Illumina NovaSeq 6000). n = 3 biological replicates per time-point and condition.