Central lactate uptake during exercise contributes to hypothalamic fibroblast growth factor 21 induction and systemic fat mobilization.

Abstract

Fibroblast growth factor 21 (FGF21) regulates lipid metabolism, and lactate may act centrally to modulate energy homeostasis. This study examined whether central FGF21 contributes to exercise-induced fat oxidation and whether central lactate regulates its induction and sympathetic-driven lipolysis. Male Wistar rats received intracerebroventricular (ICV) administration of FGF21 or lactate, or performed acute endurance exercise under three conditions: standard exercise, exercise with inhibited brain lactate transport using α-cyano-4-hydroxycinnamate (4-CIN), or exercise with reduced systemic lactate production via dichloroacetate (DCA). Cerebrospinal fluid (CSF) FGF21, central FGF21 expression, and peripheral fat oxidation indices were measured. Exercise selectively increased hypothalamic FGF21 mRNA and protein, and CSF FGF21 (all p < 0.01), without affecting cortex or hippocampus. This was accompanied by activation of p38 mitogen-activated protein kinase (p38-MAPK) and extracellular signal-regulated kinase 1/2 (ERK1/2), elevated plasma catecholamines, increased adipose cyclic adenosine monophosphate (cAMP), and enhanced hormone-sensitive lipase (HSL) phosphorylation, indicating sympathetic-driven lipolysis. ICV lactate at rest reproduced these effects via G protein-coupled receptor 81 (GPR81)-p38-MAPK signaling, whereas inhibition of p38-MAPK or GPR81 abolished lactate-induced FGF21 expression. ICV FGF21 increased catecholamines, adipose cAMP, and HSL phosphorylation, effects blocked by the FGF21 receptor antagonist BGJ-398. Inhibiting brain lactate uptake before exercise attenuated hypothalamic FGF21 induction, sympathetic activation, and fat mobilization, whereas systemic lactate reduction had a weaker effect, suggesting that brain lactate uptake contributes importantly to exercise-induced hypothalamic FGF21 regulation and fat mobilization. Taken together, these findings support a role for central lactate uptake in the activation of hypothalamic GPR81-p38-MAPK-FGF21 signaling and suggest that this pathway contributes to exercise-induced sympathetic activation and fat mobilization.