title: Resistin disrupts glycogen synthesis under high insulin and high glucose levels by down-regulating the hepatic levels of GSK3β.
abstract: The effect of mouse resistin on hepatic insulin resistance in vivo and in vitro, and its possible molecular mechanism were examined. Focusing on liver glycogen metabolism and gluconeogenesis, which are important parts of glucose metabolism, in primary cultures of rat hepatocytes we found that glycogen content was significantly lower (P<0.05) after treatment with recombinant murine resistin only in the presence of insulin plus glucose stimulation. Protein levels of factors in the insulin signaling pathway involved in glycogen synthesis were examined by Western blot analysis, with the only significant change observed being the level of phosphorylated (at Ser 9) glycogen synthase kinase-3β (GSK-3β) (P<0.001). No differences in the protein levels for the insulin receptor β (IRβ), insulin receptor substrates (IRS1 and IRS2), phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt) or their phosphorylated forms were observed between control and resistin treated primary rat hepatocytes. In a mouse model with high liver-specific expression of resistin, fasting blood glucose levels and liver glycogen content changed. Fasting blood glucose levels were significantly higher (P<0.001) in the model mice, compared to the control mice, while the glycogen content of the liver tissue was about 60% of that of the control mice (P<0.05). The gluconeogenic response was not altered between the experimental and control mice. The level of phosphorylated GSK-3β in the liver tissue was also decreased (P<0.05) in the model mice, consistent with the results from the primary rat hepatocytes. Our results suggest that resistin reduces the levels of GSK-3β phosphorylated at Ser 9 leading to impaired hepatic insulin action in primary rat hepatocytes and in a mouse model with high liver-specific expression of resistin.
authors.affiliation: Department of Pharmacology, Peking University, Health Science Center, Beijing 100191, China.
authors.forename: Rongjing
authors.initials: R
authors.lastname: Song
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.forename: Yiqing
authors.initials: Y
authors.lastname: Mao
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Zhixin
authors.initials: Z
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.forename: Tingting
authors.initials: T
authors.lastname: Guo
authors.forename: Ling
authors.initials: L
authors.lastname: Jin
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Zhang
authors.forename: Yizhuang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Na
authors.initials: N
authors.lastname: Zhou
authors.forename: Ruobi
authors.initials: R
authors.lastname: Hu
authors.forename: Jianwei
authors.initials: J
authors.lastname: Jia
authors.forename: Zhen
authors.initials: Z
authors.lastname: Lei
authors.forename: David M
authors.initials: DM
authors.lastname: Irwin
authors.forename: Gang
authors.initials: G
authors.lastname: Niu
authors.forename: Huanran
authors.initials: H
authors.lastname: Tan
mesh_terms: D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D005215:Fasting; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006946:Hyperinsulinism / Q000503:physiopathology*; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008112:Liver Glycogen / Q000096:biosynthesis*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D052243:Resistin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; C526299:Irs2 protein, rat; D008112:Liver Glycogen; D052243:Resistin; D011972:Receptor, Insulin; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3
keywords: Akt; GSK-3β; Glycogen synthase kinase-3β (GSK-3β); IRS; IRβ; Insulin resistance; Liver; PEPCK (also called PCK1); PI3K; Resistin; SOCS; TNFα; glycogen synthase kinase-3β; insulin receptor substrate; insulin receptor β; phosphoenolpyruvatecarboxykinase; phosphoinositide 3-kinase; protein kinase B; suppressors of cytokine signaling; tumor necrosis factor alpha