Hypoxic preconditioning alleviates hypoxia-induced anapyrexia by attenuating cerebral lactate elevation.

Hypoxic preconditioning (HPC) is a well-established strategy for alleviating hypoxic injury. Acute hypoxia induces a decrease in core body temperature (Tcore), a phenomenon termed hypoxia-induced anapyrexia, which may impair cellular functions and organismal vitality. Emerging evidence highlights cerebral lactate as a key mediator of hypoxia‑induced anapyrexia. This study aimed to determine whether HPC can effectively attenuate hypoxia‑induced anapyrexia and the role of cerebral lactate in this process. Using adult male rats, our results showed that HPC (11.1% O2, 2  h/d for 4 d) significantly blunted the hypoxia-induced decrease in Tcore by 58%. Mechanistically, HPC markedly suppressed the hypoxic elevation of lactate levels in cerebrospinal fluid (CSF) and upregulated the protein expression of monocarboxylate transporter 2 (MCT2) in the preoptic anterior hypothalamus (PO/AH), without affecting the expression of the lactate receptor GPR81. Intracerebroventricular injection of the MCT2 inhibitor AR‑C155858 (9  μg/μL, 1  μL) into the third ventricle (3 V) of preconditioned rats significantly elevated CSF lactate concentrations and attenuated the effect of HPC on Tcore. Similarly, 3 V injection of L‑lactate (5  mg/μL, 1  μL) or the GPR81 agonist CHBA (15  μg/μL, 1  μL) reversed the HPC-mediated alleviation of hypoxia-induced anapyrexia. Furthermore, HPC suppressed the hypoxia‑induced increase in tail temperature and decrease in interscapular brown adipose tissue temperature. HPC also significantly reduced the hypoxia-induced increase in the number of PO/AH c‑Fos+ cells, an effect abolished by MCT2 inhibition. In conclusion, these findings demonstrate that HPC effectively alleviates hypoxia‑induced anapyrexia, likely by limiting cerebral lactate accumulation through upregulation of MCT2 expression in the PO/AH.