Effect of tumor necrosis factor-alpha on insulin signal transduction in rat adipocytes: relation to PKCbeta and zeta translocation

Biochim Biophys Acta. 1999 Apr 1;1449(3):227-38. doi: 10.1016/s0167-4889(99)00016-6.

Abstract

Although much evidence has been accumulated suggesting that tumor necrosis factor-alpha (TNF-alpha) is an important mediator of insulin resistance, the precise mechanism involved is still unclear. Recently, it has been reported that insulin-induced glucose uptake is mediated by activation of second messengers such as insulin receptor substrate 1 (IRS-1), phosphatidylinositol 3-kinase (PI3K), and diacylglycerol (DG)-protein kinase C (PKC). We have examined the effect of TNF-alpha on insulin-induced glucose uptake and activations of tyrosine kinase, IRS-1, PI3K and PKC in rat adipocytes. Pretreatment with 0.1-100 nM TNF-alpha for 60 min resulted in a significant decrease in 10 nM insulin- or 1 microM 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced [3H]2-deoxyglucose uptake without affecting basal glucose uptake. 10 nM insulin-stimulated activation of tyrosine kinase, IRS-1 and PI3K was suppressed by preincubation with 0.1-10 nM TNF-alpha for 60 min. 10 nM TNF-alpha pretreatment also suppressed 10 nM insulin- and 1 microM TPA-induced increases in membrane-associated PKCbeta and PKCzeta. Furthermore, 10 nM TNF-alpha, by itself, altered PKCbeta translocation from the membrane to cytosol. These results suggest that TNF-alpha inhibits insulin-stimulated activation of both the tyrosine kinase-IRS-1-PI3K-PKCzeta pathway and DG-PKC pathway. Finally, TNF-alpha contributes to insulin resistance in rat adipocytes.

MeSH terms

  • Adipocytes / drug effects*
  • Adipocytes / metabolism
  • Animals
  • Cell Membrane / drug effects
  • Cytosol / drug effects
  • Glucose / metabolism
  • Insulin / pharmacology*
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance*
  • Isoenzymes / metabolism*
  • Male
  • Phosphoproteins / metabolism
  • Protein Kinase C / metabolism*
  • Protein Kinase C beta
  • Protein-Tyrosine Kinases / metabolism
  • Rats
  • Rats, Wistar
  • Receptor, Insulin / drug effects
  • Signal Transduction / drug effects
  • Tetradecanoylphorbol Acetate / pharmacology
  • Tumor Necrosis Factor-alpha / pharmacology*

Substances

  • Insulin
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, rat
  • Isoenzymes
  • Phosphoproteins
  • Tumor Necrosis Factor-alpha
  • Protein-Tyrosine Kinases
  • Receptor, Insulin
  • protein kinase C zeta
  • Protein Kinase C
  • Protein Kinase C beta
  • Glucose
  • Tetradecanoylphorbol Acetate