Hypoxia-induced suppression of exosomal miR-214 enhances brown adipose tissue thermogenesis via PGC-1α activation to improve systemic metabolic homeostasis

Metabolic diseases have emerged as a significant health concern in contemporary society, and the metabolic advantages of high-altitude environments are increasingly being acknowledged. Brown adipose tissue (BAT) is a crucial component that is favorable for metabolism. Our previous research has demonstrated that high-altitude hypoxic conditions can activate the activity of BAT; however, the underlying mechanisms remain unclear. This study focuses on circulating exosomes and conducts a comprehensive multi-level investigation involving human subjects, experimental animals, cells, and molecules to elucidate how hypoxic environments reprogram and regulate BAT activity through EXO-miRNAs. We employed 18 F-FDG PET-CT imaging in human subjects and observed markedly elevated BAT activity in high-altitude residents. This heightened activity was associated with better systemic glucose tolerance and improved lipid homeostasis. In mice, hypoxia stimulated thermogenesis and mitochondrial biogenesis in BAT, while also attenuating metabolic dysfunction. Omics profiling of circulating exosomes showed a pronounced reduction in miR-214 levels under hypoxic conditions in both humans and mice. Using dual-luciferase reporter assays, we further established that miR-214 directly binds the 3' untranslated region of Ppargc1α, repressing its translation. Hypoxia-driven downregulation of exosomal miR-214 relieves this repression, in turn activating the PGC-1α/UCP-1 signaling axis and promoting BAT activation. • The metabolic benefits of high-altitude hypoxia remain mechanistically unclear • High-altitude residents and mice exhibit enhanced BAT activity and improved systemic metabolism • Hypoxia downregulates exosomal miR-214 in circulation • miR-214 directly targets PGC-1α to suppress BAT thermogenesis • Inhibition of miR-214 activates the PGC-1α/UCP-1 axis and promotes metabolic health