Hypobaric hypoxia disrupts brown adipose thermogenic function in mice via Plin2 upregulation

High-altitude environments are characterized by hypobaric hypoxia and pose a significant physiological challenge. While obesity-related hypoxia is known to impair brown adipose tissue (BAT) function by suppressing lipolysis and thermogenesis, whether hypobaric hypoxia similarly compromises BAT function remains unclear. We hypothesize that, unlike obesity-associated hypoxia, hypobaric hypoxia perturbs BAT thermogenesis via a distinct mechanism involving the upregulation of Plin2.

Mice were exposed to either normoxia or hypobaric hypoxia (simulating 6000 m, 9.2% O₂) for 30 days. BAT function was assessed by analyzing lipid droplet size, lipid and triglyceride content, and expression of thermogenic protein. Thermogenic capacity was further evaluated in mice subjected to 30 days of normoxia or hypobaric hypoxia, followed by a 2-day cold exposure or 3-day treatment with the β3-adrenergic agonist CL316243. Differential proteomics and in vitro experiments were performed to explore underlying molecular mechanisms.

After 30 days of hypobaric hypoxia, mice exhibited reduced body weight (normoxia: 26.64 ± 0.91 vs. hypoxia: 21.94 ± 0.79 g, p = 0.002), yet exhibited enlarged lipid droplets in BAT (142.7 ± 15.52 vs. 387.4 ± 31.91 μm², p < 0.001) and increased lipid accumulation. Compared with normoxia, hypoxic mice displayed impaired thermogenic responses to both cold exposure and β3-adrenergic stimulation, as indicated by suppressed thermogenic gene expression. Mechanistically, hypobaric hypoxia elevated lactate levels and upregulated PPARγ, which subsequently enhanced Plin2 expression, ultimately leading to defective lipolysis and impaired thermogenesis.

We identify a novel hypoxia-lactate/PPARγ-Plin2 axis that uncouples body weight loss from BAT thermogenesis under hypobaric hypoxia. This pathway represents a previously unrecognized therapeutic target for counteracting metabolic dysfunction induced by high-altitude exposure.