title: Integrated regulation of hepatic metabolism by fibroblast growth factor 21 (FGF21) in vivo.
abstract: Fibroblast growth factor (FGF21) plays an important role in regulating hepatic oxidation of fatty acids and gluconeogenesis in response to fasting and during consumption of a ketogenic diet. However, the metabolic pathways through which FGF21 regulates hepatic function are not well defined. To identify the effects of FGF21 on the liver in vivo, we administered FGF21 to mice and analyzed acute effects on signaling and gene expression. We found that FGF21 acts directly on the liver to stimulate phosphorylation of fibroblast growth factor receptor substrate 2 and ERK1/2. Acute FGF21 treatment induced hepatic expression of key regulators of gluconeogenesis, lipid metabolism, and ketogenesis including glucose-6-phosphatase, phosphoenol pyruvate carboxykinase, 3-hydroxybutyrate dehydrogenase type 1, and carnitine palmitoyltransferase 1α. In addition, injection of FGF21 was associated with decreased circulating insulin and free fatty acid levels. FGF21 treatment induced mRNA and protein expression of peroxisome proliferator-activated receptor-γ coactivator (PGC-1α), suggesting that PGC-1α may play a role in regulating FGF21 action. However, studies using mice with liver-specific ablation of PGC-1α revealed the same regulation of gluconeogenic gene expression by FGF21 as seen in wild-type mice, indicating that PGC-1α is not necessary for the effect of FGF21 on glucose metabolism. These data demonstrate that FGF21 acts directly on the liver to modulate hepatic metabolism. The direct effects we examined are not dependent on PGC-1α. In addition, FGF21 treatment is associated with decreased serum insulin levels that my affect hepatic function.
authors.affiliation: Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Ffolliott M
authors.initials: FM
authors.lastname: Fisher
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Estall
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Adams
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Antonellis
authors.forename: Holly A
authors.initials: HA
authors.lastname: Bina
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Flier
authors.forename: Alexei
authors.initials: A
authors.lastname: Kharitonenkov
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Spiegelman
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Maratos-Flier
mesh_terms: D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000502:physiology*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000502:physiology; D005943:Gluconeogenesis; D006801:Humans; D000090265:Klotho Proteins; D008099:Liver / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008297:Male; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D047493:PPAR alpha / Q000502:physiology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; C538995:KLB protein, human; D008565:Membrane Proteins; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D048049:Extracellular Signal-Regulated MAP Kinases; D000090265:Klotho Proteins