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

• Published in: Neuroscience 2024-01, Vol.536, p.119-130
• Main Authors: Yang, Tian, Wang, Zejun, Li, Junxia, Shan, Fabo, Huang, Qing-Yuan
• Format: Article
• Language: English
• Subjects: anapyrexia; body core temperature; GPR81; hypoxia; lactate
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2023.11.012

[Display omitted] •Hypoxia induces a drop in Tcore.•Inhibition of central lactate production by DCA alleviates hypoxia-induced anapyrexia.•Activation of lactate receptor GPR81 by CHBA decreases Tcore under normoxia.•Central lactate-GPR81 signaling affects c-Fos+ cell numbers in the PO/AH.•Hypoxia raises central lactate, activates PO/AH cells via GPR81, leads to anapyrexia. Hypoxia-induced anapyrexia is thought to be a regulated decrease in body core temperature (Tcore), 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 Tcore. 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 Tcore 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 Tcore 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.