Fibroblast growth factor 21 and exercise-induced hepatic mitochondrial adaptations

Fletcher JA, Linden MA, Sheldon RD, Meers GM, Morris EM, Butterfield A, Perfield JW 2nd, Thyfault JP, Rector RS. Fibroblast growth factor 21 and exercise-induced hepatic mitochondrial adaptations. Am J Physiol Gastrointest Liver Physiol 310: G832-G843, 2016. First published March 24, 2016; doi:10.1152/ajpgi.00355.2015.-Exercise stimulates hepatic mitochondrial adaptations; however, the mechanisms remain largely unknown. Here we tested whether FGF21 plays an obligatory role in exercise induced hepatic mitochondrial adaptations by testing exercise responses in FGF21 knockout mice. FGF21 knockout (FGF21-KO) and wild-type (WT) mice (11-12 wk of age) had access to voluntary running wheels for exercise (EX) or remained sedentary for 8 wk. FGF21 deficiency resulted in greater body weight, adiposity, serum cholesterol, insulin, and glucose concentrations compared with WT mice (P < 0.05). In addition, hepatic mitochondrial complete palmitate oxidation, beta-hydroxyacyl-CoA dehydrogenase (beta-HAD) activity, and nuclear content of PGC-1 alpha were 30-50% lower in FGF21-KO mice compared with WT mice (P < 0.01). EX effectively lowered body weight, adiposity, serum triglycerides, free fatty acids, and insulin and normalized mitochondrial complete palmitate oxidation in the FGF21-KO mice, whereas the reduced hepatic beta-HAD activity and lowered nuclear content of PGC-1 alpha in FGF21-KO mice were not restored by EX. In addition, EX increased hepatic CPT-1 alpha mRNA expression and ACC phosphorylation (a marker of increased AMPK activity) and reduced hepatic triacylglycerol content in both genotypes. However, FGF21-KO mice displayed a lower EX-induced increase in the mRNA expression of the hepatic gluconeogenic gene, PEPCK, compared with WT. In conclusion, FGF21 does not appear necessary for exercise-induced systemic and hepatic mitochondrial adaptations, but the increased adiposity, hyperinsulinemia, and impairments in hepatic mitochondrial function induced by FGF21 deficiency can be partially rescued by daily wheel running exercise.