title: Fibroblast growth factor 21 and exercise-induced hepatic mitochondrial adaptations.
abstract: 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, β-hydroxyacyl-CoA dehydrogenase (β-HAD) activity, and nuclear content of PGC-1α 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 β-HAD activity and lowered nuclear content of PGC-1α in FGF21-KO mice were not restored by EX. In addition, EX increased hepatic CPT-1α 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.
authors.affiliation: Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri; Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri;
authors.forename: Justin A
authors.initials: JA
authors.lastname: Fletcher
authors.affiliation: Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri; Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri;
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Linden
authors.affiliation: Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri; Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri;
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Sheldon
authors.affiliation: Department of Medicine-Division of Gastroenterology and Hepatology, University of Missouri, Columbia, Missouri; Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri;
authors.forename: Grace M
authors.initials: GM
authors.lastname: Meers
authors.affiliation: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas; and.
authors.forename: E Matthew
authors.initials: EM
authors.lastname: Morris
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana;
authors.forename: Anthony
authors.initials: A
authors.lastname: Butterfield
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana;
authors.forename: James W
authors.initials: JW
authors.lastname: Perfield
authors.affiliation: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas; and Kansas City Veterans Affairs Medical Center, Research Service, Kansas, City, Missouri.
authors.forename: John P
authors.initials: JP
authors.lastname: Thyfault
authors.affiliation: Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri; Department of Medicine-Division of Gastroenterology and Hepatology, University of Missouri, Columbia, Missouri; Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, Missouri; rectors@health.missouri.edu.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Rector
mesh_terms: D000222:Adaptation, Physiological; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001823:Body Composition; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D005943:Gluconeogenesis; D007328:Insulin / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000378:metabolism*; D010168:Palmitates / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D012420:Running
chemical_list: D001786:Blood Glucose; D007328:Insulin; D010168:Palmitates; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D002784:Cholesterol; D002334:Carnitine O-Palmitoyltransferase
keywords: exercise; metabolism; mitochondria; mitochondrial function