Exercise, FGF21, and PGC-1 : roles in hepatic metabolism

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] The liver is instrumental in maintaining euglycemia during times of fasting and exercise, and in-turn exercise is a stimulus that challenges the liver and results in hepatic mitochondrial adaptations. Mechanisms responsible for these improvements in mitochondrial function are not currently known. Fibroblast growth factor 21 (FGF21), a powerful metabolic regulator, is one potential mechanism responsible for exercise- induced hepatic mitochondrial adaptations. Previous studies show that FGF21 modulates hepatic fatty acid oxidation (FAO), gluconeogenesis, ketogenesis, and TCA cycle flux, in addition to gene transcription of proteins important to these processes. The purpose of the first objective in the current study was to examine whether FGF21 is necessary for exercise to induce hepatic mitochondrial adaptations in mice. A second objective was to determine if PGC--1? is responsible for the upregulation of genes important to metabolic processes in response to FGF21 signaling. We mechanistically assessed the necessity of FGF21 for exercise-induced hepatic mitochondrial adaptations by providing wild-type and FGF21 knockout mice with running wheels for 8 weeks to promote physical activity. A major finding in the current study is that the FGF21KO mice experience a hepatic fatty acid oxidation deficit compared to the wild-type group and that 8 weeks of voluntary wheel running normalized FAO in the FGF21KO mice. The role of PGC-1[alpha] in FGF21 regulation of gene transcription was also assessed by continuously administering FGF21 (1 mg/kg), or saline into wild-type or liver specific PGC--1[alpha] heterozygous mice (LPGC--1[alpha]) for 4 weeks. It was found that female mice did not express a phenotype effect; however, in male mice hepatic FAO was significantly blunted in the LPGC-1[alpha] mice, yet FGF21 administration was able to elevate FAO regardless in both genotypes. Collectively, this data suggests that FGF21 is necessary for the expression and content of certain genes or proteins, but that VWR is able to circumvent the absence of FGF21 and normalize hepatic FAO. Furthermore, a reduction in hepatic PGC-1[alpha] does not appear to influence the ability of FGF21 to regulate hepatic FAO.