THIAZOLIDINEDIONES BLOCK TUMOR NECROSIS FACTOR-ALPHA-INDUCED INHIBITION OF INSULIN SIGNALING

TNF-alpha has been shown to be an important mediator of insulin resist ance linked to obesity, This cytokine induces insulin resistance, at l east in part, through inhibition of the tyrosine kinase activity of th e insulin receptor. Recently, a new class of compounds, the antidiabet ic thiazolidinediones (TZDs), has been shown to improve insulin resist ance in obesity and non-insulin-dependent diabetes mellitus in both ro dents and man, Here we show that TZDs have powerful effects on the abi lity of TNF-alpha to alter the most proximal steps of insulin signalin g, including tyrosine phosphorylation of the insulin receptor and its major substrate, IRS-1, and activation of PI3-kinase. Troglitazone or pioglitazone essentially eliminate the reduction in tyrosine phosphory lation of IR and IRS-1 caused by TNF-alpha in fat cells, even at relat ively high doses (25 ng/ml). That this effect of TZDs operates through activation of the nuclear receptor PPAR gamma/RXR complex is shown by the fact that similar effects are observed with other PPAR gamma/RXR ligands such as 15 deoxy Delta(12,14)PGJ2 and LG268. The TZDs do not i nhibit all TNF-alpha signaling in that the transcription factor NF-kB is still induced well. These data indicate that TZDs can specifically block certain actions of TNF-alpha related to insulin resistance, sugg esting that this block may contribute to their antidiabetic actions.