title: Hepatic overexpression of a dominant negative form of raptor enhances Akt phosphorylation and restores insulin sensitivity in K/KAy mice.
abstract: 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-DeltaC(T)), was overexpressed in the liver via injection of its adenovirus into the circulation. Hepatic raptor-DeltaC(T) expression levels were 1.5- to 4-fold that of endogenously expressed raptor. Glucose tolerance in raptor-DeltaC(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-DeltaC(T) overexpressing mice. In addition, insulin-induced IRS-1, Ser(307), and Ser(636/639) phosphorylations were significantly suppressed in the raptor-DeltaC(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-DeltaC(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.
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Koketsu
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sakoda
authors.forename: Midori
authors.initials: M
authors.lastname: Fujishiro
authors.forename: Akifumi
authors.initials: A
authors.lastname: Kushiyama
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fukushima
authors.forename: Hiraku
authors.initials: H
authors.lastname: Ono
authors.forename: Motonobu
authors.initials: M
authors.lastname: Anai
authors.forename: Takako
authors.initials: T
authors.lastname: Kikuchi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Fukuda
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kamata
authors.forename: Nanao
authors.initials: N
authors.lastname: Horike
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Uchijima
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kurihara
authors.forename: Tomoichiro
authors.initials: T
authors.lastname: Asano
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002460:Cell Line; D018014:Gene Transfer Techniques; D018149:Glucose Intolerance / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology*; D007668:Kidney / Q000166:cytology; D008099:Liver / Q000502:physiology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008817:Mice, Mutant Strains; D046912:Multiprotein Complexes; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D010766:Phosphorylation; D011506:Proteins; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D046912:Multiprotein Complexes; D011506:Proteins; D014157:Transcription Factors; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases