Fibroblast growth factor-21 promotes glucose uptake through activation of the serum response factor/ Ets-like protein-1 signaling cascade in Adipocytes

Abstract

RESULTS: Fibroblast Growth Factor-21 (FGF-21) is a liver-secreted endocrine factor with multiple beneficial effects on obesity-related disorders. Several previous studies indicated that FGF-21 induces glucose uptake by inducing the expression of glucose transporter-1 (GLUT1) in adipocytes. However, the molecular events underlying its actions in adipocyte remain poorly characterized. Here we investigated the signalling pathways that mediate FGF21-induced GLUT1 expression in vitro and in animals. Quantitative real-time PCR and luciferase reporter assay showed that FGF-21 induced GLUT1 expression through transcriptional activation. Suppression of the protein kinase ERK1/2 by its pharmacological inhibitor PD98059 abolished FGF21-induced glucose uptake and transactivation of the GLUT1 gene, indicating that FGF-21 transactivates GLUT1 through ERK1/2. The luciferase reporter assay demonstrated that truncation of -3174 bp to -3105 bp of the GLUT1 promoter, which contains two highly conserved Serum Response Element (SRE) and E-Twenty Six (ETS) binding motifs, dramatically decreased the promoter activity of the GLUT1 gene. Furthermore, mutations in either of these two core elements completely abolished the promoter activity of GLUT1. Chromatin immunoprecipitation (ChIP) assay demonstrated that the transcription factors Serum Response Factor (SRF) and Ets-like protein-1 (Elk-1), both of which are the downstream targets of ERK1/2, were recruited to the GLUT1 promoter upon FGF-21 stimulation. Explant studies on epididymal fats showed that FGF21-evoked phosphorylation of ERK/12, expression of GLUT1 and glucose uptake in high fat diet-induced obese mice were significantly attenuated compared to lean littermates, implying the presence of a FGF-21 resistant state in obese adipose tissue. In conclusion, FGF-21 induces GLUT1 expression through sequential activation of ERK1/2 and SRF/Elk-1, which in turn triggers the transcription of GLUT1 to enhance glucose uptake in adipocytes. The present findings highlight the potential of FGF-21 as a drug target for obesity-related metabolic diseases.