OBJECTIVE Mice genetically deficient in endothelial nitric oxide synthase (Nos3-/-) have fasting hyperinsulinemia and hepatic insulin resistance, indicating the importance of Nos3 (nitric oxide synthase) in maintaining metabolic homeostasis. Although the current paradigm holds that these metabolic effects are derived specifically from the expression of Nos3 in the endothelium, it has been established that bone marrow-derived cells also express Nos3. The aim of this study was to investigate whether bone marrow-derived cell Nos3 is important in maintaining metabolic homeostasis. Approach and Results: To test the hypothesis that bone marrow-derived cell Nos3 contributes to metabolic homeostasis, we generated chimeric male mice deficient or competent for Nos3 expression in circulating blood cells. These mice were placed on a low-fat diet for 5 weeks, a time period which is known to induce hepatic insulin resistance in global Nos3-deficient mice but not in wild-type C57Bl/6 mice. Surprisingly, we found that the absence of Nos3 in the bone marrow-derived component is associated with hepatic insulin resistance and that restoration of Nos3 in the bone marrow-derived component in global Nos3-deficient mice is sufficient to restore hepatic insulin sensitivity. Furthermore, we found that overexpression of Nos3 in bone marrow-derived component in wild-type mice attenuates the development of hepatic insulin resistance during high-fat feeding. Finally, compared with wild-type macrophages, the loss of macrophage Nos3 is associated with increased inflammatory responses to lipopolysaccharides and reduced anti-inflammatory responses to IL-4, a macrophage phenotype associated with the development of hepatic and systemic insulin resistance. CONCLUSIONS These results would suggest that the metabolic and hepatic consequences of high-fat feeding are mediated by loss of Nos3/nitric oxide actions in bone marrow-derived cells, not in endothelial cells.

中文翻译：

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造血细胞表达的内皮型一氧化氮可保护肝脏免受胰岛素抵抗。

目的遗传上缺乏内皮型一氧化氮合酶（Nos3-/-）的小鼠具有空腹高胰岛素血症和肝胰岛素抵抗性，表明Nos3（一氧化氮合酶）在维持代谢稳态方面的重要性。尽管目前的范例认为这些代谢作用特别是由内皮中Nos3的表达引起的，但已经确定骨髓来源的细胞也表达Nos3。这项研究的目的是调查骨髓源性Nos3在维持代谢稳态方面是否重要。方法和结果：为了检验骨髓来源的Nos3有助于代谢稳态的假设，我们产生了嵌合的雄性小鼠，其在循环血细胞中缺乏或具有Nos3表达的能力。将这些小鼠低脂饮食放置5周，已知在整体Nos3缺陷型小鼠中诱导肝胰岛素抵抗但在野生型C57Bl / 6小鼠中诱导肝胰岛素抗性的时间段。出人意料的是，我们发现骨髓来源的成分中Nos3的缺失与肝胰岛素抵抗有关，而全球Nos3缺陷型小鼠的骨髓来源的成分中Nos3的恢复足以恢复肝胰岛素敏感性。此外，我们发现野生型小鼠骨髓来源的成分中Nos3的过表达减弱了高脂喂养过程中肝胰岛素抵抗的发展。最后，与野生型巨噬细胞相比，巨噬细胞Nos3的丢失与对脂多糖的炎症反应增加以及对IL-4的抗炎反应减少有关，与肝和全身胰岛素抵抗发展有关的巨噬细胞表型。结论这些结果表明，高脂喂养的代谢和肝脏后果是由骨髓来源的细胞而不是内皮细胞中Nos3 /一氧化氮作用的丧失介导的。