Hepatic overexpression of a dominant negative form of raptor enhances Akt phosphorylation and restores insulin sensitivity in K/KAy mice
Hepatic overexpression of a dominant negative form of raptor enhances Akt phosphorylation and restores insulin sensitivity in K/KAy mice
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DOI：
10.1152/ajpendo.00253.2007
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发表时间：
2008-04-01
影响因子：
5.1
通讯作者：
Asano, Tomoichiro
中科院分区：
文献类型：
--
作者：
Koketsu, Yuko;Sakoda, Hideyuki;Asano, Tomoichiro
据报道，几种丝氨酸/苏氨酸激酶磷酸化IRS-1的丝氨酸残基，从而诱导胰岛素抵抗。在这项研究中，为了研究mTOR/raptor对具有遗传性肥胖相关胰岛素抵抗的K/KAy小鼠中胰岛素信号传导和代谢的影响，通过将其腺病毒注射到循环中，在肝脏中过表达显性阴性raptor，COOH末端缺失的raptor（raptor-Delta C-T）。肝脏raptor-Δ C-T表达水平是内源性表达raptor的1.5至4倍。与LacZ过表达小鼠相比，raptor-Delta C-T过表达小鼠的葡萄糖耐量显著改善。胰岛素诱导的p70 S6激酶（p70（S6 k））的激活在raptor-Delta C-T过表达小鼠的肝脏中被显著抑制。此外，胰岛素诱导的IRS-1、Ser（307）和Ser 636/639磷酸化在raptor-Delta C-T过表达的肝脏中被显著抑制，而IRS-1的酪氨酸磷酸化增加。PI 3-激酶激活响应胰岛素刺激增加约两倍，Akt磷酸化明显增强基础和胰岛素刺激条件下的猛禽-Delta C-T小鼠的肝脏。因此，我们的数据表明，mTOR/p70 S6 k通路的抑制导致K/KAy小鼠中葡萄糖耐量的改善。这些观察结果可能有助于开发新的抗糖尿病药物。
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-Delta C-T), was overexpressed in the liver via injection of its adenovirus into the circulation. Hepatic raptor-Delta C-T expression levels were 1.5- to 4-fold that of endogenously expressed raptor. Glucose tolerance in raptor-Delta 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-Delta C-T overexpressing mice. In addition, insulin-induced IRS-1, Ser(307), and Ser636/639 phosphorylations were significantly suppressed in the raptor-Delta 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-Delta C-T mice. Thus, our data indicate that suppression of the mTOR/p70S6k pathway leads to improved glucose tolerance in K/KAy mice. These observations may contribute to the development of novel antidiabetic agents.