Rapamycin Modulates Markers of Mitochondrial Biogenesis and Fatty Acid Oxidation in the Adipose Tissue of db/db Mice.
Rapamycin Modulates Markers of Mitochondrial Biogenesis and Fatty Acid Oxidation in the Adipose Tissue of db/db Mice.
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发表时间：
2013-06
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通讯作者：
S. S. Deepa-S.;Michael E Walsh;R. Hamilton;D. Pulliam;Yun Shi;Shauna Hill;Yan Li;H. Van Remmen
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作者：
S. S. Deepa-S.;Michael E Walsh;R. Hamilton;D. Pulliam;Yun Shi;Shauna Hill;Yan Li;H. Van Remmen
营养摄取过量会导致肥胖、胰岛素抵抗和2型糖尿病。哺乳动物雷帕霉素靶点（mTOR）是营养感应途径的主要组成部分，也调节线粒体氧化功能。雷帕霉素是一种mTOR的药理学抑制剂，可引起葡萄糖耐受不良并抑制线粒体氧化功能。虽然许多研究都集中在雷帕霉素对对照野生型小鼠的影响上，但我们的研究是第一个研究雷帕霉素对糖尿病血脂异常模型db/db小鼠线粒体基因表达和胰岛素敏感性的影响。从2月龄开始，雌性db/+和db/db小鼠自由饲喂含有雷帕霉素的饮食或对照饮食6个月。每月测量体重、脂肪量、瘦体重和食物摄入量。研究雷帕霉素和对照日粮对大鼠性腺白色脂肪组织（WAT）脂肪生成、脂肪酸氧化和线粒体生物生成指标以及不同血清参数的影响。采用胰岛素耐量试验测定全身胰岛素敏感性。与对照组相比，雷帕霉素喂养db/db小鼠的体重（58%）和脂肪量（33%）下降，WAT脂肪酸氧化和线粒体生物发生标志物升高，循环非酯化游离脂肪酸（NEFA）减少，循环脂联素升高，胰岛素敏感性改善。这些数据表明，雷帕霉素在db/db小鼠中具有抗肥胖作用，改善全身胰岛素敏感性，并提示在小鼠中同时抑制mTOR和瘦素信号的意想不到的效果。
Excess nutrient uptake leads to obesity, insulin resistance, and type 2 diabetes. Mammalian target of the rapamycin (mTOR), a major component of the nutrient-sensing pathway also regulates mitochondrial oxidative function. Rapamycin, a pharmacological inhibitor of mTOR, causes glucose intolerance and inhibits mitochondrial oxidative function. While a number of studies have focused on the effect of rapamycin on control wild-type mice, ours is the first to study the effect of rapamycin on mitochondrial gene expression and insulin sensitivity in the db/db mouse, a model of diabetic dyslipidemia. Female db/+ and db/db mice were fed ad libitum a rapamycin-containing diet or a control diet for 6 months, starting at two months of age. Body weight, fat mass, lean mass and food intake were measured monthly. Effect of rapamycin or control diet on markers of adipogenesis, fatty acid oxidation and mitochondrial biogenesis in the gonadal white adipose tissue (WAT) as well as different serum parameters were assessed. Whole body insulin sensitivity was measured by insulin tolerance test. Rapamycin feeding to db/db mice decreased body weight (58%) and fat mass (33%), elevated markers of fatty acid oxidation and mitochondrial biogenesis in WAT, reduced circulating non-esterified free fatty acids (NEFA), elevated circulating adiponectin and improved insulin sensitivity, compared to control diet fed db/db mice. These data demonstrate that rapamycin exhibits an anti-obesity effect and improves whole body insulin sensitivity in db/db mice and suggest an unexpected effect of simultaneous inhibition mTOR and leptin signaling in mice.