p66Shc-generated Oxidative Signal Promotes Fat Accumulation
p66Shc-generated Oxidative Signal Promotes Fat Accumulation
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DOI：
10.1074/jbc.m804362200
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发表时间：
2008-12-05
影响因子：
4.8
通讯作者：
Giorgio, Marco
中科院分区：
文献类型：
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作者：
Berniakovich, Ina;Trinei, Mirella;Giorgio, Marco
脂肪组织中的活性氧（ROS）和胰岛素信号是衰老和年龄相关疾病的关键决定因素。然而，尚不清楚它们是独立的因素，还是在机械上有联系。我们以p66（Shc）基因敲除小鼠为模型系统，研究了ROS对胰岛素信号转导的影响。p66（Shc）是一种氧化还原酶，在哺乳动物中产生线粒体ROS并促进衰老。我们报告说，胰岛素激活氧化还原酶活性的p66（Shc），特别是在脂肪细胞和p66（Shc）产生的活性氧调节胰岛素信号通过多种机制，包括AKT磷酸化，Foxo定位，和选定的胰岛素靶基因的调节。缺失p66（Shc）导致脂肪细胞中线粒体解偶联增加和甘油三酯积累减少，体内代谢率增加，脂肪量减少和对饮食诱导的肥胖的抵抗力降低。此外，p66（Shc-/-）小鼠表现出隔热受损。这些发现表明，p66（Shc）产生的ROS调节胰岛素对小鼠能量代谢的影响，并表明细胞内氧化应激可能通过促进脂肪沉积和脂肪相关疾病加速衰老。
Reactive oxygen species (ROS) and insulin signaling in the adipose tissue are critical determinants of aging and age-associated diseases. It is not clear, however, if they represent independent factors or they are mechanistically linked. We investigated the effects of ROS on insulin signaling using as model system the p66(Shc)-null mice. p66(Shc) is a redox enzyme that generates mitochondrial ROS and promotes aging in mammals. We report that insulin activates the redox enzyme activity of p66(Shc) specifically in adipocytes and that p66(Shc)-generated ROS regulate insulin signaling through multiple mechanisms, including AKT phosphorylation, Foxo localization, and regulation of selected insulin target genes. Deletion of p66(Shc) resulted in increased mitochondrial uncoupling and reduced triglyceride accumulation in adipocytes and in vivo increased metabolic rate and decreased fat mass and resistance to diet-induced obesity. In addition, p66(Shc-/-) mice showed impaired thermo-insulation. These findings demonstrate that p66(Shc)-generated ROS regulate the effect of insulin on the energetic metabolism in mice and suggest that intracellular oxidative stress might accelerate aging by favoring fat deposition and fat-related disorders.