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

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.