Hepatic overexpression of a dominant negative form of raptor enhances Akt phosphorylation and restores insulin sensitivity in K/KAy mice

Several serine/threonine kinases reportedly phosphorylate serine residues of IRS-1 and thereby induce insulin resistance. In this study, to investigate the effect of mTOR/raptor on insulin signaling and metabolism in K/KAy mice with genetic obesity-associated insulin resistance, a dominant negative raptor, COOH-terminally deleted raptor (raptor-ΔCT), was overexpressed in the liver via injection of its adenovirus into the circulation. Hepatic raptor-ΔCT expression levels were 1.5- to 4-fold that of endogenously expressed raptor. Glucose tolerance in raptor-ΔCT-overexpressing mice improved significantly compared with that of LacZ-overexpressing mice. Insulin-induced activation of p70S6 kinase (p70S6k) was significantly suppressed in the livers of raptor-ΔCT overexpressing mice. In addition, insulin-induced IRS-1, Ser307, and Ser636/639 phosphorylations were significantly suppressed in the raptor-ΔCT-overexpressing liver, whereas tyrosine phosphorylation of IRS-1 was increased. PI 3-kinase activation in resp...