title: Increased insulin receptor substrate-1 and enhanced skeletal muscle insulin sensitivity in mice lacking CCAAT/enhancer-binding protein beta.
abstract: CCAAT/enhancer-binding protein beta (C/EBPbeta) controls gene transcription and metabolic processes in a variety of insulin-sensitive tissues; however, its role in regulating insulin responsiveness in vivo has not been investigated. We performed hyperinsulinemic-euglycemic clamps in awake, non-stressed, chronically catheterized adult mice homozygous for a deletion in the gene for C/EBPbeta (C/EBPbeta(-/-)). Fasting plasma insulin, glucose, and free fatty acid (FFA) levels were significantly lower in C/EBPbeta(-/-) mice compared with wild-type (WT) controls. Acute hyperinsulinemia (4 h) suppressed hepatic glucose production, phosphoenolpyruvate carboxykinase mRNA, and plasma FFA to a similar extent in WT and C/EBPbeta(-/-) mice, suggesting that C/EBPbeta deletion does not alter the metabolic and gene regulatory response to insulin in liver and adipose tissue. In contrast, using submaximal (5 milliunits/kg/min) and maximal (20 milliunits/kg/min) insulin infusions, whole-body glucose disposal was 77% (p < 0.01) and 33% (p < 0.05) higher in C/EBPbeta(-/-) mice, respectively, compared with WT mice. Maximal insulin-stimulated 3-O-methylglucose uptake in isolated soleus muscle was 54% greater in C/EBPbeta(-/-) mice (p < 0.05). Furthermore, insulin-stimulated insulin receptor and Akt Ser(473) phosphorylation and phosphatidylinositol 3-kinase activity were 1.6-2.5-fold greater in skeletal muscle from C/EBPbeta(-/-) mice compared with WT mice. The level of insulin receptor substrate-1 protein was increased 2-fold in skeletal muscle from C/EBPbeta(-/-) mice. These results demonstrate that C/EBPbeta deletion decreases plasma FFA levels and increases insulin signal transduction specifically in skeletal muscle, and both contribute to increased whole-body insulin sensitivity.
authors.affiliation: Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4935, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Shao
authors.forename: P
authors.initials: P
authors.lastname: Muhlenkamp
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.forename: P
authors.initials: P
authors.lastname: Klepcyk
authors.forename: J
authors.initials: J
authors.lastname: Ren
authors.forename: J E
authors.initials: JE
authors.lastname: Friedman
mesh_terms: D000273:Adipose Tissue; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D005947:Glucose / Q000096:biosynthesis / Q000378:metabolism; D007328:Insulin / Q000378:metabolism* / Q000502:physiology; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics*; D010750:Phosphoproteins / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D009687:Nuclear Proteins; D010750:Phosphoproteins; D005947:Glucose