Effect of tumor necrosis factor-α on insulin signal transduction in rat adipocytes: relation to PKCβ and ζ translocation

Abstract

Although much evidence has been accumulated suggesting that tumor necrosis factor-α (TNF-α) 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-α 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-α for 60 min resulted in a significant decrease in 10 nM insulin- or 1 μM 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-α for 60 min. 10 nM TNF-α pretreatment also suppressed 10 nM insulin- and 1 μM TPA-induced increases in membrane-associated PKCβ and PKCζ. Furthermore, 10 nM TNF-α, by itself, altered PKCβ translocation from the membrane to cytosol. These results suggest that TNF-α inhibits insulin-stimulated activation of both the tyrosine kinase-IRS-1-PI3K-PKCζ pathway and DG-PKC pathway. Finally, TNF-α contributes to insulin resistance in rat adipocytes.