Acceleration of Lactate Uptake and Utilization Contributes to Neuroprotective Action of <scp>FGF21</scp> Involved in Naturally Aging Mice

Brain aging is characterized by neuroinflammation and lactate metabolic changes. However, the functional role of FGF21 in the aging brain and its influence on lactate homeostasis remains unclear until now. In the study, male C57BL/6 mice were divided into 2-month-old (control), 20-month (aging), and FGF21-treated aging mice (FGF21). We also examined the MAPK signals and astrocyte-neuron lactate shuttle (ANLS) proteins in wild-type and hydroxycarboxylic acid receptor 1-knockout (HCA1-KO) mice with aging or long-term L-lactate infusion. In a mouse model of aging, neuronal FGF21 expression and ANLS rate were upregulated in hippocampal and cortical regions. Administration of exogenous FGF21 (1 mg/kg) to aging or lactate-infused mice can significantly improve learning and memory performance and the lactate metabolic microenvironment in an MCT2-dependent manner. Besides, HCA1-KO can significantly abolish both the CREB and MAPK signaling activation in lactate-infused mice, which differs from the scenario of aging mice. Furthermore, in vitro aging model further confirmed that p38-mediated FGF21 production and PI3K-mTOR-dependent MCT2 protein translation process, respectively. The increase in levels of FGF21 protein as the brain ages might help neurons cope with age-related neuroinflammation and lactate accumulation in mice. Our findings indicated that the shuttle rate of lactate and its microenvironment are related to neuronal function, which may be one therapeutic target for aging-related cognitive dysfunction.