title: Fibroblast growth factor 21 induces glucose transporter-1 expression through activation of the serum response factor/Ets-like protein-1 in adipocytes.
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.
authors.affiliation: Department of Medicine, University of Hong Kong, Hong Kong, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Ge
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Hui
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Karen S L
authors.initials: KS
authors.lastname: Lam
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D020816:Amino Acid Motifs; D000818:Animals; D001483:Base Sequence; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D051246:Glucose Transport Proteins, Facilitative / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese / Q000378:metabolism; D008969:Molecular Sequence Data; D012694:Serine / Q000737:chemistry; D026362:Serum Response Factor / Q000378:metabolism*; D015398:Signal Transduction; D050807:ets-Domain Protein Elk-1 / Q000096:biosynthesis*
chemical_list: D051246:Glucose Transport Proteins, Facilitative; D026362:Serum Response Factor; D050807:ets-Domain Protein Elk-1; C414620:fibroblast growth factor 21; D012694:Serine; D005346:Fibroblast Growth Factors