Cerebral Lactate Participates in Hypoxia-induced Anapyrexia Through its Receptor G Protein-coupled Receptor 81

Hypoxia-induced anapyrexia is thought to be a regulated decrease in body core temperature (T_core), but the underlying mechanism remains unclear. Recent evidence suggests that lactate, a glycolysis product, could modulate neuronal excitability through the G protein-coupled receptor 81 (GPR81). The present study aims to elucidate the role of central lactate and GPR81 in a rat model of hypoxia-induced anapyrexia. The findings revealed that hypoxia (11.1% O₂, 2 h) led to an increase in lactate in cerebrospinal fluid (CSF) and a decrease in T_core. Injection of dichloroacetate (DCA, 5 mg/kg, 1 μL), a lactate production inhibitor, to the third ventricle (3 V), alleviated the increase in CSF lactate and the decrease in T_core under hypoxia. Immunofluorescence staining showed GPR81 was expressed in the preoptic area of hypothalamus (PO/AH), the physiological thermoregulation integration center. Under normoxia, injection of GPR81 agonist 3-chloro-5-hydroxybenzoic acid (CHBA, 0.05 mg/kg, 1 μL) to the 3 V, reduced T_core significantly. In addition, hypoxia led to a dramatic increase in tail skin temperature and a decrease in interscapular brown adipose tissue skin temperature. The number of c-Fos⁺ cells in the PO/AH increased after exposure to 11.1% O₂ for 2 h, but administration of DCA to the 3 V blunted this response. Injection of CHBA to the 3 V also increased the number of c-Fos⁺ cells in the PO/AH under normoxia. In light of these, our research has uncovered the pivotal role of central lactate-GPR81 signaling in anapyrexia, thereby providing novel insights into the mechanism of hypoxia-induced anapyrexia.