Intermittent Hypoxia Drives Early Metabolic Dysfunction in Brown Adipose Tissue
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Background
Obstructive sleep apnea (OSA) is associated with metabolic dysfunction, yet the early impact of intermittent hypoxia (IH)—a defining feature of OSA—on brown adipose tissue (BAT) remains unclear.
Methods
We investigated the direct and early effects of IH on BAT using both in vitro and in vivo approaches. Differentiated mouse brown adipocytes were exposed to IH for 48 hours and analyzed for β3-adrenergic signaling, lipolysis, and thermogenic activation. Complementary in vivo studies assessed transcriptomic, morphological, and functional changes in BAT, white adipose tissue (WAT), and liver after 1 or 4 weeks of IH exposure in mice.
Results
IH blunted β3-adrenergic signaling in cultured brown adipocytes, leading to reduced phosphorylation of key signaling proteins, impaired lipolytic response, and decreased expression of UCP1. In vivo, BAT exhibited early and sustained transcriptomic rewiring characterized by downregulation of pathways related to fatty acid metabolism, oxidative phosphorylation, and peroxisomal function. These molecular changes were accompanied by abnormal lipid droplet enlargement and a reduced lipolytic response to adrenergic stimulation. In contrast, WAT showed transient gene expression changes, and the liver displayed a delayed and robust transcriptomic response evident only after four weeks of IH exposure. Despite these metabolic alterations, thermogenic responses to cold challenge remained intact in IH-treated mice.
Conclusions
BAT is uniquely and rapidly affected by intermittent hypoxia, undergoing functional, molecular, and morphological changes within one week of exposure. These alterations precede systemic inflammation and metabolic dysfunction, positioning BAT dysfunction as an early event in the pathogenesis of OSA-associated metabolic disease.
