Submitted on April 28, 2007
Accepted on February 11, 2008
Hepatic overexpression of a dominant negative form of Raptor enhances Akt phosphorylation and restores insulin resistance in K/KAy mice
Yuko Koketsu1, Hideyuki Sakoda1, Midori Fujishiro1, Akifumi Kushiyama1, Yasushi Fukushima2, Hiraku Ono3, Motonobu Anai4, Takako Kikuchi1, Takeshi Fukuda1, Hideaki Kamata5, Nanao Horike6, Yasunobu Uchijima7, Hiroki Kurihara7, and Tomoichiro Asano8*
1 Internal Medicine, University of Tokyo, Tokyo, Japan
2 Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
3 Internal Medicine, University of Tokyo, Japan
4 the Institute for Adult Disease, Asahi Life Foundation, Tokyo, Japan
5 Department of Medical Science, Graduate School of Medicine, The University of Hiroshima, Japan
6 Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, Japan
7 Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
8 Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan; Department of Medical Science, University of Hiroshima, Hiroshima, Japan
* To whom correspondence should be addressed. E-mail: asano-tky{at}umin.ac.jp.
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, C terminally deleted Raptor (Raptor-
CT), was overexpressed in the liver via injection of its adenovirus into the circulation. Hepatic Raptor-CT expression levels were 1.5-4 fold that of endogenously expressed Raptor. Glucose tolerance in Raptor-CT overexpressing mice improved significantly as compared with that of LacZ overexpressing mice. Insulin-induced activation of p70S6K was significantly suppressed in the livers of Raptor-CT overexpressing mice. In addition, insulin-induced IRS-1, Ser307 and Ser636/639 phosphorylations were significantly suppressed in the Raptor-CT overexpressing liver, whereas tyrosine phosphorylation of IRS-1 was increased. PI 3-kinase activation in response to insulin stimulation was increased approximately two-fold, and Akt phosphorylation was clearly enhanced under both basal and insulin-stimulated conditions in the livers of Raptor-CT mice. Thus, our data indicate that suppression of the mTOR/p70 S6 kinase pathway leads to improved glucose tolerance in K/KAy mice. These observations may contribute to the development of novel anti-diabetic agents.
