An in Vivo Model for Elucidation of the Mechanism of Tumor Necrosis Factor- (TNF- )-Induced Insulin Resistance: Evidence for Differential Regulation of Insulin Signaling by TNF-

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Abstract
Tumor necrosis factor-a (TNF-a) has been shown to induce in- sulin resistance in cultured cells as well as in animal models. The aim of this study was to map the in vivo mechanism whereby TNF-a contributes to the pathogenesis of impaired insulin signaling, us- ing obese and lean Zucker rats in which TNF-a activity was in- hibited through adenovirus-mediated gene transfer. We employed a replication-incompetent adenovirus-5 (Ad5) vector to endog- enously express a TNF inhibitor (TNFi) gene, which encodes a chimeric protein consisting of the extracellular domain of the hu- man 55-kDa TNF receptor joined to a mouse IgG heavy chain. Control animals consisted of rats infected with the same titer of adenovirus carrying the lac-z complementary DNA, encoding for b-galactosidase. There was a significant reduction in plasma in- sulin and free fatty acid levels in TNFi obese rats 2 days following Ad5 administration. The peripheral insulin sensitivity index was 50% greater, whereas hepatic glucose output was completely sup- pressed during hyperinsulinemic glucose clamps in TNFi obese animals, with no differences observed between the two lean groups. The improvement in peripheral and hepatic sensitivity to insulin seen in the obese animals was independent of insulin receptor (IR) number and insulin binding affinity for IR. However, TNF-a neu- tralization led to a 2.5-fold increase in tyrosine phosphorylation of IR in skeletal muscle, whereas this was unchanged in liver. There was also a 4-fold increase in particulate protein tyrosine phospha- tase activity of skeletal muscle in TNFi obese animals vs. b-ga- lactosidase controls, whereas protein tyrosine phosphatase activity in liver was unchanged. These results suggest that TNF-a is a mediator of insulin resistance in obesity and may modulate IR signaling in skeletal muscle and liver through different pathways. TNF-a may affect insulin action in the liver either at sites distal to the IR or indirectly, possibly because of increased provision of gluconeogenic substrates or altered counterregulation. In addition, the Ad5-mediated gene delivery system employed here provides an in vivo model that is efficient and economical for exploring mech- anisms involved in TNF-a-induced insulin resistance in various genetic models of obesity-linked diabetes. (Endocrinology 139: 4928 - 4935, 1998

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