Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle
Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle
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DOI：
10.1038/nm1001-1138
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发表时间：
2001-10-01
期刊：
影响因子：
82.9
通讯作者：
Marette, A
中科院分区：
文献类型：
--
作者：
Perreault, M;Marette, A
诱导型一氧化氮合酶（iNOS）是由骨骼肌和脂肪中的炎性细胞因子诱导的。已经提出，慢性诱导型一氧化氮合酶诱导可能导致肌肉胰岛素抵抗。在这里，我们表明，iNOS的表达增加的肌肉和脂肪的遗传和饮食模型的肥胖。此外，编码iNOS的基因被破坏的小鼠（Nos 2（-/-）小鼠）被保护免于高脂肪诱导的胰岛素抵抗。然而野生型和Nos 2（-/-）小鼠在高脂饮食下都发展为肥胖，肥胖的Nos 2（-/-）小鼠表现出改善的葡萄糖耐量、正常的体内胰岛素敏感性和正常的胰岛素刺激的肌肉葡萄糖摄取。肥胖野生型小鼠中iNOS的诱导与肌肉中胰岛素对磷脂酰肌醇3-激酶和Akt激活的损伤有关。这些缺陷在肥胖的Nos 2（-/-）小鼠中被完全预防。这些发现提供了基因证据，表明iNOS参与了饮食诱导的肥胖症中肌肉胰岛素抵抗的发展。
Inducible nitric oxide synthase (iNOS) is induced by inflammatory cytokines in skeletal muscle and fat. It has been proposed that chronic iNOS induction may cause muscle insulin resistance. Here we show that iNOS expression is increased in muscle and fat of genetic and dietary models of obesity. Moreover, mice in which the gene encoding iNOS was disrupted (Nos2(-/-) mice) are protected from high-fat-induced insulin resistance. Whereas both wild-type and Nos2(-/-) mice developed obesity on the high-fat diet, obese Nos2(-/-) mice exhibited improved glucose tolerance, normal insulin sensitivity in vivo and normal insulin-stimulated glucose uptake in muscles. iNOS induction in obese wild-type mice was associated with impairments in phosphatidylinositol 3-kinase and Akt activation by insulin in muscle. These defects were fully prevented in obese Nos2(-/-) mice. These findings provide genetic evidence that iNOS is involved in the development of muscle insulin resistance in diet-induced obesity.