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

## TL;DR

Chronic intermittent hypoxia from sleep apnea disrupts daily metabolic rhythms in the liver and body, shifting metabolism to conserve oxygen.

## Contribution

The study reveals how chronic hypoxia acts as a circadian zeitgeber, reprogramming metabolic pathways through the cAMP-CREB1 pathway.

## Key findings

- Chronic IH alters circadian regulation of glucose, lipid, and redox metabolism in a time-specific manner.
- Metabolic shifts include increased gluconeogenesis, glycogen turnover, and lipid mobilization during hypoxia.
- The cAMP-CREB1 pathway is identified as a key driver of circadian transcriptional changes in the liver.

## 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.

Sleep apnea reprograms circadian metabolism.