AN IN-VIVO MODEL FOR ELUCIDATION OF THE MECHANISM OF TUMOR-NECROSIS-FACTOR-ALPHA (TNF-ALPHA)-INDUCED INSULIN-RESISTANCE - EVIDENCE FOR DIFFERENTIAL REGULATION OF INSULIN SIGNALING BY TNF-ALPHA

Tumor necrosis factor-alpha (TNF-alpha) has been shown to induce insul in resistance in cultured cells as well as in animal models. The aim o f this study was to map the in vivo mechanism whereby TNF-alpha contri butes to the pathogenesis of impaired insulin signaling, using obese a nd lean Zucker rats in which TNF-alpha activity was inhibited through adenovirus-mediated gene transfer. We employed a replication-incompete nt adenovirus-5 (Ad5) vector to endogenously express a TNF inhibitor ( TNFi) gene, which encodes a chimeric protein consisting of the extrace llular domain of the human 55-kDa TNF receptor joined to a mouse IgG h eavy chain. Control animals consisted of rats infected with the same t iter of adenovirus carrying the lac-z complementary DNA, encoding for beta-galactosidase. There was a significant reduction in plasma insuli n and free fatty acid levels in TNFi obese rats 2 days following Ad5 a dministration. The peripheral insulin sensitivity index was 50% greate r, whereas hepatic glucose output was completely suppressed during hyp erinsulinemic glucose clamps in TNFi obese animals, with no difference s observed between the two lean groups.