Adenosine triphosphate (ATP), an important signaling molecule, participates in various pathophysiological processes via the activation of purinergic-receptors. Recent studies have shown that the expression and function of purinergic-receptors (P2-receptors) could be altered in diabetic or hyperinsulinemia conditions To characterize the effect of ATP on insulin signaling, we treated primary rat adipocytes with varied concentrations of ATP The pre-treatment led to impaired insulin signaling, i e blunted phosphorylation in Insulin Receptor Substrate-1 (IRS-1) tyrosine and Protein Kinase B (PKB) Ser473 in response to insulin treatment, when ATP concentration reached 1 mM We then observed that ATP dose-dependently reduced the level of 1 kappa B. a negative regulator of inflammatory response Consistently, IRS-1 Ser307 phosphorylation in response to insulin treatment, a site for inflammatory pathway to interfere insulin signaling, was enhanced by ATP Furthermore, effects of ATP on insulin signaling and I kappa B content were blocked by P2-receptor inhibition Finally, insulin-stimulated glucose uptake was impaired by ATP in adipocytes but not in the L6 muscle cells This study therefore shows for the first time the involvement of ATP-evoked P2-receptor activation in mediating the inflammatory response and the generation of insulin resistance in adipocytes (C) 2010 Elsevier Inc All rights reserved