Fibroblast growth factor 21 induces glucose transporter-1 expression through activation of the serum response factor/Ets-like protein-1 in adipocytes

J Biol Chem. 2011 Oct 7;286(40):34533-41. doi: 10.1074/jbc.M111.248591. Epub 2011 Aug 16.

Abstract

Fibroblast growth factor 21 (FGF21) is a liver-secreted endocrine factor with multiple beneficial effects on obesity-related disorders. It enhances glucose uptake by inducing the expression of glucose transporter-1 (GLUT1) in adipocytes. Here we investigated the signaling pathways that mediate FGF21-induced GLUT1 expression and glucose uptake in vitro and in animals. Quantitative real-time PCR and a luciferase reporter assay showed that FGF21 induced GLUT1 expression through transcriptional activation. The truncation of the GLUT1 promoter from -3145 to -3105 bp, which contains two highly conserved serum response element (SRE) and E-Twenty Six (ETS) binding motif, dramatically decreased FGF21-induced promoter activity of the GLUT1 gene. A chromatin immunoprecipitation assay demonstrated that the transcription factors serum response factor (SRF) and Ets-like protein-1 (Elk-1) were recruited to the GLUT1 promoter upon FGF21 stimulation. The siRNA-mediated knockdown of either SRF or Elk-1 resulted in a marked attenuation in FGF21-induced GLUT1 expression and glucose uptake in adipocytes. In C57 lean mice, a single intravenous injection of FGF21 induced phosphorylation of Elk-1 at Ser(383) and SRF at Ser(103) and also led to the recruitment of Elk-1 and SRF to the GLUT1 promoter in epididymal fats. By contrast, such effects of in vivo FGF21 administration were blunted in high fat diet-induced obese mice. In conclusion, FGF21 induces GLUT1 expression and glucose uptake through sequential activation of ERK1/2 and SRF/Elk-1, which in turn triggers the transcriptional activation of GLUT1 in adipocytes. The impairment in this signaling pathway may contribute to FGF21 resistance in obese mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / metabolism*
  • Amino Acid Motifs
  • Animals
  • Base Sequence
  • Fibroblast Growth Factors / metabolism*
  • Gene Expression Regulation*
  • Glucose Transport Proteins, Facilitative / biosynthesis*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese / metabolism
  • Molecular Sequence Data
  • Serine / chemistry
  • Serum Response Factor / metabolism*
  • Signal Transduction
  • ets-Domain Protein Elk-1 / biosynthesis*

Substances

  • Glucose Transport Proteins, Facilitative
  • Serum Response Factor
  • ets-Domain Protein Elk-1
  • fibroblast growth factor 21
  • Serine
  • Fibroblast Growth Factors