Silencing of FGF-21 expression promotes hepatic gluconeogenesis and glycogenolysis by regulation of the STAT3-SOCS3 signal

FEBS J. 2014 May;281(9):2136-47. doi: 10.1111/febs.12767. Epub 2014 Apr 1.


Insulin resistance is a metabolic disorder associated with type 2 diabetes. Recent reports have shown that fibroblast growth factor-21 (FGF-21) plays an important role in the progression of insulin resistance. However, the biochemical and molecular mechanisms by which changes in FGF-21 activation result in changes in the rates of hepatic gluconeogenesis and glycogenolysis remain to be elucidated. In this study, we developed adenovirus-mediated shRNA against FGF-21 to inhibit FGF-21 expression in ApoE knockout mice. Using this mouse model, we determined the effects of FGF-21 knockdown in vivo on hepatic glucose production, gluconeogenesis and glycogenolysis, and their relationship with the signal transducer and activator of transcription 3 (STAT3)/suppressor of cytokine signaling 3 (SOCS3) signal pathways. We show that liver-specific knockdown of FGF-21 in high-fat diet-fed ApoE knockout mice resulted in a 39% increase in glycogenolysis and a 75% increase in gluconeogenesis, accompanied by increased hepatic expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. Furthermore, FGF-21 knockdown decreased phosphorylation of STAT3 and SOCS3 expression in high-fat diet-fed mice. Our data suggest that hepatic FGF-21 knockdown increases gluconeogenesis and glycogenolysis by activation of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase via the STAT3/SOCS3 pathway, ultimately leading to exacerbation of hepatic insulin resistance.

Keywords: FGF-21 knockdown; SOCS3; STAT3; insulin resistance; liver glucose fluxes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Fibroblast Growth Factors / blood
  • Fibroblast Growth Factors / genetics
  • Fibroblast Growth Factors / physiology*
  • Gene Silencing*
  • Gluconeogenesis / genetics*
  • Glycogenolysis / genetics*
  • Homeostasis
  • Insulin Resistance
  • Liver / metabolism*
  • Mice
  • Mice, Knockout
  • RNA Interference
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction*
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins / metabolism*


  • STAT3 Transcription Factor
  • Socs3 protein, mouse
  • Stat3 protein, mouse
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • fibroblast growth factor 21
  • Fibroblast Growth Factors