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首页> 外文期刊>Circulation research: a journal of the American Heart Association >Deletion of protein tyrosine phosphatase 1b improves peripheral insulin resistance and vascular function in obese, leptin-resistant mice via reduced oxidant tone.
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Deletion of protein tyrosine phosphatase 1b improves peripheral insulin resistance and vascular function in obese, leptin-resistant mice via reduced oxidant tone.

机译：蛋白质酪氨酸磷酸酶1b的缺失可通过降低氧化张力改善肥胖，瘦素抵抗小鼠的外周胰岛素抵抗和血管功能。

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RATIONALE: Obesity is a risk factor for cardiovascular dysfunction, yet the underlying factors driving this impaired function remain poorly understood. Insulin resistance is a common pathology in obese patients and has been shown to impair vascular function. Whether insulin resistance or obesity, itself, is causal remains unclear. OBJECTIVE: The present study tested the hypothesis that insulin resistance is the underlying mediator for impaired NO-mediated dilation in obesity by genetic deletion of the insulin-desensitizing enzyme protein tyrosine phosphatase (PTP)1B in db/db mice. METHODS AND RESULTS: The db/db mouse is morbidly obese, insulin-resistant, and has tissue-specific elevation in PTP1B expression compared to lean controls. In db/db mice, PTP1B deletion improved glucose clearance, dyslipidemia, and insulin receptor signaling in muscle and fat. Hepatic insulin signaling in db/db mice was not improved by deletion of PTP1B, indicating specific amelioration of peripheral insulin resistance. Additionally, obese mice demonstrate an impaired endothelium dependent and independent vasodilation to acetylcholine and sodium nitroprusside, respectively. This impairment, which correlated with increased superoxide in the db/db mice, was corrected by superoxide scavenging. Increased superoxide production was associated with increased expression of NAD(P)H oxidase 1 and its molecular regulators, Noxo1 and Noxa1. CONCLUSIONS: Deletion of PTP1B improved both endothelium dependent and independent NO-mediated dilation and reduced superoxide generation in db/db mice. PTP1B deletion did not affect any vascular function in lean mice. Taken together, these data reveal a role for peripheral insulin resistance as the mediator of vascular dysfunction in obesity.
机译：理由：肥胖是心血管功能障碍的危险因素，但导致这种功能受损的根本因素仍知之甚少。胰岛素抵抗是肥胖患者的常见病状，已被证实会损害血管功能。胰岛素抵抗或肥胖本身是否是因果关系尚不清楚。目的：本研究检验了以下假设：胰岛素抵抗是通过在db / db小鼠中胰岛素脱敏酶蛋白酪氨酸磷酸酶（PTP）1B的基因缺失而导致肥胖症中NO介导的扩张受损的潜在介质。方法和结果：db / db小鼠病态肥胖，胰岛素抵抗，与瘦对照组相比，PTP1B表达具有组织特异性升高。在db / db小鼠中，PTP1B缺失改善了肌肉和脂肪中的葡萄糖清除率，血脂异常以及胰岛素受体信号传导。 db / db小鼠的肝胰岛素信号传导不能通过删除PTP1B来改善，表明外周胰岛素抵抗的特异性改善。另外，肥胖小鼠分别表现出对乙酰胆碱和硝普钠的内皮依赖性和非依赖性血管舒张受损。这种损伤与db / db小鼠中超氧化物的增加有关，通过超氧化物清除得以纠正。超氧化物产量的增加与NAD（P）H氧化酶1及其分子调节剂Noxo1和Noxa1表达的增加有关。结论：删除PTP1B改善了db / db小鼠的内皮依赖性和独立性NO介导的扩张，并减少了过氧化物的产生。 PTP1B删除不影响任何瘦小鼠的血管功能。综上所述，这些数据揭示了外周胰岛素抵抗作为肥胖中血管功能障碍的介质的作用。

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