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Silencing of FGF ‐21 expression promotes hepatic gluconeogenesis and glycogenolysis by regulation of the STAT 3– SOCS 3 signal
Author(s) -
Wang Cong,
Dai Jihuan,
Yang Mengliu,
Deng Guangjiang,
Xu Shengnan,
Jia Yanjun,
Boden Guenther,
Ma Zhongmin A.,
Yang Gangyi,
Li Ling
Publication year - 2014
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12767
Subject(s) - socs3 , glycogenolysis , gluconeogenesis , phosphoenolpyruvate carboxykinase , fgf21 , endocrinology , medicine , gene knockdown , insulin resistance , biology , stat protein , signal transduction , stat3 , insulin , chemistry , fibroblast growth factor , microbiology and biotechnology , biochemistry , metabolism , receptor , apoptosis , enzyme
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 sh RNA 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 ( STAT 3)/suppressor of cytokine signaling 3 ( SOCS 3) 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 STAT 3 and SOCS 3 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 STAT 3/ SOCS 3 pathway, ultimately leading to exacerbation of hepatic insulin resistance.