Interleukin-1beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression

Endocrinology. 2007 Jan;148(1):241-51. doi: 10.1210/en.2006-0692. Epub 2006 Oct 12.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / drug effects*
  • Adipocytes / immunology*
  • Adipocytes / metabolism
  • Animals
  • Down-Regulation / drug effects
  • Down-Regulation / immunology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • GTPase-Activating Proteins / metabolism
  • Gene Expression / drug effects
  • Gene Expression / immunology
  • Glucose / metabolism
  • Glucose Transporter Type 1 / genetics
  • Glucose Transporter Type 1 / metabolism
  • Glucose Transporter Type 4 / genetics
  • Glucose Transporter Type 4 / metabolism
  • Inflammation / immunology
  • Inflammation / metabolism
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance / immunology*
  • Interleukin-1beta / immunology*
  • Interleukin-1beta / pharmacology*
  • Interleukin-6 / pharmacology
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / immunology
  • Mice
  • Mice, Obese
  • Phosphoproteins / genetics*
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Tyrosine / metabolism

Substances

  • GTPase-Activating Proteins
  • Glucose Transporter Type 1
  • Glucose Transporter Type 4
  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Interleukin-1beta
  • Interleukin-6
  • Irs1 protein, mouse
  • Phosphoproteins
  • Slc2a1 protein, mouse
  • Slc2a4 protein, mouse
  • Tbc1d4 protein, mouse
  • Tyrosine
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Glucose