Tumor necrosis factor-alpha causes insulin receptor substrate-2-mediated insulin resistance and inhibits insulin-induced adipogenesis in fetal brown adipocytes

Endocrinology. 1998 Mar;139(3):1229-38. doi: 10.1210/endo.139.3.5854.


Treatment of fetal brown adipocytes with 0.6 nM tumor necrosis factor (TNF)-alpha for 24 h resulted in a partial impairment in the expression of fatty acid synthase, glycerol-3-phosphate dehydrogenase, and glucose transporter (GLUT)-4 messenger RNAs (mRNAs), as well as in the enhancement in the cytoplasmic lipid content in response to insulin. However, the expression of the tissue-specific gene, uncoupling protein 1, is increased by the presence of TNF-alpha. The antiadipogenic effect of TNF-alpha was accompanied by a down-regulation of CCAAT/enhancer-binding protein-alpha and beta mRNAs and up-regulation of CCAAT/enhancer-binding protein-delta, with the expression of peroxisome proliferator-activated receptor-gamma remaining essentially unmodified. Moreover, TNF-alpha caused an insulin resistance on the insulin-induced glucose uptake in brown adipocytes. Pretreatment with TNF-alpha resulted in hypophosphorylation of the insulin receptor in response to insulin, without affecting the number of insulin receptors per cell or its molecular mass. However, insulin receptor substrate (IRS)-1 and IRS-2 signaling in response to insulin showed functional differences. Thus, TNF-alpha pretreatment induced a hypophosphorylation of IRS-2 but not of IRS-1. This effect leads to an impairment in the IRS-2-associated phosphatidylinositol (PI) 3-kinase activation due to a decreased association of alpha-p85 regulatory subunit of PI 3-kinase with IRS-2 but not in the IRS-1-associated PI 3-kinase activation in response to insulin. Our results indicate that TNF-alpha induced an IRS-2- but not IRS-1-mediated insulin resistance on glucose transport and lipid synthesis in fetal brown adipocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes / drug effects*
  • Adipocytes / metabolism
  • Adipose Tissue, Brown / drug effects*
  • Adipose Tissue, Brown / metabolism
  • Animals
  • CCAAT-Enhancer-Binding Proteins
  • Cells, Cultured
  • DNA-Binding Proteins / physiology
  • Female
  • Glucose / metabolism
  • Glucose Transporter Type 4
  • Insulin / pharmacology*
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance*
  • Intracellular Signaling Peptides and Proteins
  • Monosaccharide Transport Proteins / genetics
  • Monosaccharide Transport Proteins / physiology
  • Muscle Proteins*
  • Nuclear Proteins / physiology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoproteins / physiology*
  • Pregnancy
  • Rats
  • Rats, Wistar
  • Receptors, Cytoplasmic and Nuclear / physiology
  • Transcription Factors / physiology
  • Tumor Necrosis Factor-alpha / pharmacology*


  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins
  • Glucose Transporter Type 4
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Intracellular Signaling Peptides and Proteins
  • Irs2 protein, rat
  • Monosaccharide Transport Proteins
  • Muscle Proteins
  • Nuclear Proteins
  • Phosphoproteins
  • Receptors, Cytoplasmic and Nuclear
  • Slc2a4 protein, rat
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Phosphatidylinositol 3-Kinases
  • Glucose