title: FGF15/19 regulates hepatic glucose metabolism by inhibiting the CREB-PGC-1α pathway.
abstract: Regulation of hepatic carbohydrate homeostasis is crucial for maintaining energy balance in the face of fluctuating nutrient availability. Here, we show that the hormone fibroblast growth factor 15/19 (FGF15/19), which is released postprandially from the small intestine, inhibits hepatic gluconeogenesis, like insulin. However, unlike insulin, which peaks in serum 15 min after feeding, FGF15/19 expression peaks approximately 45 min later, when bile acid concentrations increase in the small intestine. FGF15/19 blocks the expression of genes involved in gluconeogenesis through a mechanism involving the dephosphorylation and inactivation of the transcription factor cAMP regulatory element-binding protein (CREB). This in turn blunts expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) and other genes involved in hepatic metabolism. Overexpression of PGC-1α blocks the inhibitory effect of FGF15/19 on gluconeogenic gene expression. These results demonstrate that FGF15/19 works subsequent to insulin as a postprandial regulator of hepatic carbohydrate homeostasis.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Potthoff
authors.forename: Jamie
authors.initials: J
authors.lastname: Boney-Montoya
authors.forename: Mihwa
authors.initials: M
authors.lastname: Choi
authors.forename: Tianteng
authors.initials: T
authors.lastname: He
authors.forename: Nishanth E
authors.initials: NE
authors.lastname: Sunny
authors.forename: Santhosh
authors.initials: S
authors.lastname: Satapati
authors.forename: Kelly
authors.initials: K
authors.lastname: Suino-Powell
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
authors.forename: Robert D
authors.initials: RD
authors.lastname: Gerard
authors.forename: Brian N
authors.initials: BN
authors.lastname: Finck
authors.forename: Shawn C
authors.initials: SC
authors.lastname: Burgess
authors.forename: David J
authors.initials: DJ
authors.lastname: Mangelsdorf
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kliewer
mesh_terms: D000818:Animals; D002952:Citric Acid Cycle / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors*; D005227:Fatty Acids / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000494:pharmacology* / Q000502:physiology; D015870:Gene Expression; D020869:Gene Expression Profiling; D017930:Genes, Reporter; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D005227:Fatty Acids; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C108526:fibroblast growth factor 15, mouse; D005346:Fibroblast Growth Factors; D008156:Luciferases; D005947:Glucose