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- Title
Hepatic Overexpression of Dominant Negative Form of mTOR Enhances Akt Phosphorylation and Restores Insulin Resistance in K/KAy Mice.
- Authors
Koketsu, Yuko; Sakoda, Hideyuki; Fujishiro, Midori; Kushiyama, Aki-Fumi; Kikuchi, Takako; Fukuda, Takeshi; Asano, Tomoichiro
- Abstract
Several serine/threonine kinases reportedly phosphorylate serine residues of IRS-1, and thereby induce insulin resistance. In this study, we examined the contribution of an effecter of mammalian target of rapamycin (mTOR) in the insulin resistance of a genetic obesity-associated insulin resistant K/KAy mice. To investigate the effect of mTOR on the insulin signaling and metabolism in K/KAy mice, a dominant-negative Raptor, C terminally deleted Raptor (Raptor-ACT), was overexpressed in the liver by injection of its adenovirus into the circulation. Then, we performed intraperitoneal glucose tolerance test (IPGTT), and insulin signaling assays including IRS-1 phosphorylation, phosphatidylinositol 3-kinase (PI3K), Akt phosphorylation and p70 $6 kinase in the liver of the mice. The expression levels of Raptor-ACT were over twice those of endogenously expressed Raptor. Glucose tolerance of Raptor-ΔACT mice were improved significantly compared with that of LacZ mice. Insulin-induced activation of p70S6K was significantly suppressed in the liver of Raptor-ΔACT overexpressing mice. In addition, insulin-induced IRS-I Ser636/639 phosphorylation was significantly suppressed in the Raptor-ΔCT overexpressing liver, whereas tyrosine phosphorylation of IRS-1 increased. PI 3-kinase activation in response to insulin stimulation was enhanced approximately twice, and Akt phosphorylation was clearly enhanced in both basal and insulin-stimulated conditions in the liver of Raptor-ΔCT mice. Our data indicate that suppression of mTOR/p70 $6 kinase pathway leads to the improved glucose tolerance in the K/KAy mice, and may be conducive to develop novel anti-diabetic agents.
- Publication
Diabetes, 2007, Vol 56, pA35
- ISSN
0012-1797
- Publication type
Academic Journal