Lactate signals through hepatic fibroblast growth factor 21 to facilitate exercise-induced lipid mobilization

Fibroblast growth factor 21 (FGF21) is a liver-derived hormone that enhances metabolic flexibility. This study investigated whether Fibroblast growth factor 21 (FGF21) contributes to lipolysis and lipid mobilization during exercise and whether exercise-induced hyperlactatemia is required for FGF21-mediated lipid mobilization. Male Wistar rats were assigned to control, exercise (EX), lactate (LAC), recombinant FGF21 (FGF21), and exercise with dichloroacetate (EXDCA) groups to attenuate exercise-induced hyperlactatemia. Serum metabolites and tissue gene and protein expression were assessed. Acute exercise increased serum FGF21, elevated hepatic FGF21 expression, and selectively upregulated FGFR1/β-Klotho in subcutaneous fat. These responses were accompanied by higher circulating FFA and glycerol and increased adipose triglyceride lipase (ATGL), phosphorylated hormone-sensitive lipase (ser660) (p-HSL ser660 ), AMP-activated protein kinase alpha 1 (AMPKα1), phosphorylated AMPKα (Thr172) (p-AMPKα Thr172 ) expression and cAMP concentration. Recombinant FGF21 administration similarly increased adipose receptor expression and lipolytic gene activation but did not induce hepatic FGF21. Lactate administration was associated with elevated serum FGF21 and hepatic FGF21, AMPKα1, and p-AMPKα Thr172 , but did not stimulate lipolysis. Attenuation of exercise-induced hyperlactatemia in EXDCA group blunted the rise in serum FGF21, reduced hepatic FGF21 expression, and decreased adipose FGFR1 and β-Klotho, accompanied by lower plasma triglycerides. Lactate is suggested to bean upstream regulator of hepatic FGF21 release and is associated with FGF21-related lipolytic responses and lipid mobilization during exercise.