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This Article Full Text Full Text (PDF) All Versions of this Article: 294/4/E719    most recent 00253.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Koketsu, Y. Articles by Asano, T. PubMed PubMed Citation Articles by Koketsu, Y. Articles by Asano, T.

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

¹Department of Internal Medicine, Graduate School of Medicine, University of Tokyo; ²Institute for Adult Disease, Asahi Life Foundation; ³Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, University of Tokyo, Tokyo; and ⁴Department of Medical Science, Graduate School of Medicine, University of Hiroshima, Hiroshima, Japan

Submitted 28 August 2007 ; accepted in final form 11 February 2008

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-C_T), was overexpressed in the liver via injection of its adenovirus into the circulation. Hepatic raptor-C_T expression levels were 1.5- to 4-fold that of endogenously expressed raptor. Glucose tolerance in raptor-C_T-overexpressing mice improved significantly compared with that of LacZ-overexpressing mice. Insulin-induced activation of p70S6 kinase (p70^S6k) was significantly suppressed in the livers of raptor-C_T overexpressing mice. In addition, insulin-induced IRS-1, Ser³⁰⁷, and Ser^636/639 phosphorylations were significantly suppressed in the raptor-C_T-overexpressing liver, whereas tyrosine phosphorylation of IRS-1 was increased. PI 3-kinase activation in response to insulin stimulation was increased approximately twofold, and Akt phosphorylation was clearly enhanced under both basal and insulin-stimulated conditions in the livers of raptor-C_T mice. Thus, our data indicate that suppression of the mTOR/p70^S6k pathway leads to improved glucose tolerance in K/KAy mice. These observations may contribute to the development of novel antidiabetic agents.

insulin receptor substrate-1; insulin resistance