Overexpression of endothelial nitric oxide synthase prevents diet-induced obesity and regulates adipocyte phenotype.
Overexpression of endothelial nitric oxide synthase prevents diet-induced obesity and regulates adipocyte phenotype.
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DOI：
10.1161/circresaha.112.266395
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发表时间：
2012-10-12
影响因子：
20.1
通讯作者：
Hill BG
中科院分区：
文献类型：
--
作者：
Sansbury BE;Cummins TD;Tang Y;Hellmann J;Holden CR;Harbeson MA;Chen Y;Patel RP;Spite M;Bhatnagar A;Hill BG
内皮功能障碍是动物模型和人类中糖尿病和肥胖症的特征性特征。内皮型一氧化氮合酶（eNOS）产生一氧化氮的缺陷与胰岛素抵抗有关，高脂饮食会加剧胰岛素抵抗。然而，尚未研究增加eNOS水平的代谢作用。目前的研究旨在测试eNOS的过度表达是否会预防饮食诱导的肥胖和胰岛素抵抗。在db/db小鼠和高脂喂养的野生型（WT）C57 BL/6 J小鼠中，脂肪组织中eNOS蛋白的丰度降低，骨骼肌或主动脉中eNOS水平无显著变化。过度表达eNOS的小鼠（eNOS-TG小鼠）对饮食诱导的肥胖和高胰岛素血症有抵抗力，尽管全身性葡萄糖耐受不良基本上未受影响。与WT小鼠相比，高脂喂养的eNOS-TG小鼠显示出更高的代谢率和减弱的白色脂肪细胞肥大。eNOS过表达不影响食物消耗或饮食诱导的血浆胆固醇或瘦素水平的变化，但血浆甘油三酯和脂肪酸减少。脂肪组织的代谢组学分析表明，eNOS过度表达主要影响氨基酸和脂质代谢;亚途径分析表明脂肪酸氧化的变化。与这些发现一致，eNOS-TG小鼠的脂肪组织显示出更高水平的PPAR-α和PPAR-γ基因表达，线粒体蛋白丰度升高，以及更高的耗氧率。这些发现表明，eNOS活性的增加防止了高脂肪饮食的致肥胖作用，而不影响全身胰岛素抵抗，部分是通过刺激脂肪组织中的代谢活性。
Endothelial dysfunction is a characteristic feature of diabetes and obesity in animal models and humans. Deficits in nitric oxide production by endothelial nitric oxide synthase (eNOS) are associated with insulin resistance, which is exacerbated by high fat diet. Nevertheless, the metabolic effects of increasing eNOS levels have not been studied. The current study was designed to test whether overexpression of eNOS would prevent diet-induced obesity and insulin resistance. In db/db mice and in high fat-fed wild-type (WT) C57BL/6J mice, the abundance of eNOS protein in adipose tissue was decreased without significant changes in eNOS levels in skeletal muscle or aorta. Mice overexpressing eNOS (eNOS-TG mice) were resistant to diet-induced obesity and hyperinsulinemia, although systemic glucose intolerance remained largely unaffected. In comparison with WT mice, high fat-fed eNOS-TG mice displayed a higher metabolic rate and attenuated hypertrophy of white adipocytes. Overexpression of eNOS did not affect food consumption or diet-induced changes in plasma cholesterol or leptin levels, yet plasma triglycerides and fatty acids were decreased. Metabolomic analysis of adipose tissue indicated that eNOS overexpression primarily affected amino acid and lipid metabolism; subpathway analysis suggested changes in fatty acid oxidation. In agreement with these findings, adipose tissue from eNOS-TG mice showed higher levels of PPAR-α and PPAR–γ gene expression, elevated abundance of mitochondrial proteins, and a higher rate of oxygen consumption. These findings demonstrate that increased eNOS activity prevents the obesogenic effects of high fat diet without affecting systemic insulin resistance, in part, by stimulating metabolic activity in adipose tissue.