title: Interleukin-1beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression.
abstract: Inflammation is associated with obesity and insulin resistance. Proinflammatory cytokines produced by adipose tissue in obesity could alter insulin signaling and action. Recent studies have shown a relationship between IL-1beta level and metabolic syndrome or type 2 diabetes. However, the ability of IL-1beta to alter insulin signaling and action remains to be explored. We demonstrated that IL-1beta slightly increased Glut 1 translocation and basal glucose uptake in 3T3-L1 adipocytes. Importantly, we found that prolonged IL-1beta treatment reduced the insulin-induced glucose uptake, whereas an acute treatment had no effect. Chronic treatment with IL-1beta slightly decreased the expression of Glut 4 and markedly inhibited its translocation to the plasma membrane in response to insulin. This inhibitory effect was due to a decrease in the amount of insulin receptor substrate (IRS)-1 but not IRS-2 expression in both 3T3-L1 and human adipocytes. The decrease in IRS-1 amount resulted in a reduction in its tyrosine phosphorylation and the alteration of insulin-induced protein kinase B activation and AS160 phosphorylation. Pharmacological inhibition of ERK totally inhibited IL-1beta-induced down-regulation of IRS-1 mRNA. Moreover, IRS-1 protein expression and insulin-induced protein kinase B activation, AS160 phosphorylation, and Glut 4 translocation were partially recovered after treatment with the ERK inhibitor. These results demonstrate that IL-1beta reduces IRS-1 expression at a transcriptional level through a mechanism that is ERK dependent and at a posttranscriptional level independently of ERK activation. By targeting IRS-1, IL-1beta is capable of impairing insulin signaling and action, and could thus participate in concert with other cytokines, in the development of insulin resistance in adipocytes.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM) U568, Faculty of Medicine, Avenue de Valombrose, 06107 Nice Cedex 2, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Jager
authors.forename: Thierry
authors.initials: T
authors.lastname: Grémeaux
authors.forename: Mireille
authors.initials: M
authors.lastname: Cormont
authors.forename: Yannick
authors.initials: Y
authors.lastname: Le Marchand-Brustel
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Tanti
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology* / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008820:Mice, Obese; D010750:Phosphoproteins / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
chemical_list: D020690:GTPase-Activating Proteins; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D053583:Interleukin-1beta; D015850:Interleukin-6; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; C495678:Slc2a1 protein, mouse; C495693:Slc2a4 protein, mouse; C505647:Tbc1d4 protein, mouse; D014443:Tyrosine; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D005947:Glucose