FGF15/19 Regulates Hepatic Glucose Metabolism by Inhibiting the CREB-PGC-1α Pathway

Cell Metab. 2011 Jun 8;13(6):729-38. doi: 10.1016/j.cmet.2011.03.019.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Citric Acid Cycle / drug effects
  • Cyclic AMP Response Element-Binding Protein / antagonists & inhibitors*
  • Fatty Acids / metabolism
  • Fibroblast Growth Factors / pharmacology*
  • Fibroblast Growth Factors / physiology
  • Gene Expression
  • Gene Expression Profiling
  • Genes, Reporter
  • Gluconeogenesis
  • Glucose / metabolism*
  • Liver / drug effects
  • Liver / metabolism*
  • Luciferases / biosynthesis
  • Luciferases / genetics
  • Male
  • Metabolic Networks and Pathways
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oxidation-Reduction
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Signal Transduction
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism
  • Transcription Factors

Substances

  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Fatty Acids
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, mouse
  • Trans-Activators
  • Transcription Factors
  • fibroblast growth factor 15, mouse
  • Fibroblast Growth Factors
  • Luciferases
  • Glucose