title: Silencing of FGF-21 expression promotes hepatic gluconeogenesis and glycogenolysis by regulation of the STAT3-SOCS3 signal.
abstract: 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.
authors.affiliation: Key Laboratory of Diagnostic Medicine (Ministry of Education) and Department of Clinical Biochemistry, College of Laboratory Medicine, Chongqing Medical University, 400016, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Wang
authors.forename: Jihuan
authors.initials: J
authors.lastname: Dai
authors.forename: Mengliu
authors.initials: M
authors.lastname: Yang
authors.forename: Guangjiang
authors.initials: G
authors.lastname: Deng
authors.forename: Shengnan
authors.initials: S
authors.lastname: Xu
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Jia
authors.forename: Guenther
authors.initials: G
authors.lastname: Boden
authors.forename: Zhongmin A
authors.initials: ZA
authors.lastname: Ma
authors.forename: Gangyi
authors.initials: G
authors.lastname: Yang
authors.forename: Ling
authors.initials: L
authors.lastname: Li
mesh_terms: D000818:Animals; D005346:Fibroblast Growth Factors / Q000097:blood / Q000235:genetics / Q000502:physiology*; D020868:Gene Silencing; D005943:Gluconeogenesis / Q000235:genetics*; D050261:Glycogenolysis / Q000235:genetics*; D006706:Homeostasis; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*
chemical_list: D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors
keywords: FGF-21 knockdown; SOCS3; STAT3; insulin resistance; liver glucose fluxes