Endothelial nitric oxide synthase and regulation of macrophage function

 描述(申请人提供)：肥胖影响了近一半的美国成年人口，是导致胰岛素抵抗和糖尿病的最重要的风险因素。肥胖与胰岛素靶组织(如肝脏和脂肪组织)的慢性低度炎症状态有关。在细胞水平上，巨噬细胞似乎在促进肥胖相关炎症方面发挥了重要作用。在胰岛素抵抗的发展过程中，驻留的肝巨噬细胞(Kupffer细胞)和从骨髓招募到肝脏的单核细胞(骨髓生成)被激活，并释放细胞因子和趋化因子。这些分子有助于胰岛素抵抗和2型糖尿病(T2D)的发展。更重要的是，取消这些巨噬细胞驱动的炎症介质可以减轻肥胖期间胰岛素抵抗/糖尿病的发展。不幸的是，对抗这些炎性巨噬细胞衍生介质的因素尚未确定。一氧化氮和内皮型一氧化氮合酶(eNOS或NOS3)是公认的促进血管内环境稳定的因素。然而，NOS3的缺失似乎会导致代谢紊乱，从而导致胰岛素抵抗。更具体地说，肥胖期间NOS3来源的NO的减少先于胰岛素抵抗的发展，并且NOS3基因缺失(NOS3-/-鼠)与全身和肝脏的胰岛素抵抗有关。此外，在肥胖期间恢复NO生物利用度的药物策略(例如，PDE5抑制)和增加NO产生的遗传策略(例如，NOS3过度表达)可以恢复小鼠的胰岛素敏感性。长期以来，我们的实验室和其他实验室将NOS3的有益代谢效应归因于内皮介导的血流改善，增加了营养物质向胰岛素敏感组织(如肝脏、肌肉和脂肪组织)的输送，从而促进了营养物质的利用或储存，并维持了代谢平衡。然而，我们实验室最近的工作表明，在肥胖期间，巨噬细胞NOS3-而不是内皮NOS3-通过减少巨噬细胞产生炎性细胞/趋化因子来以细胞自主的方式维持代谢稳态。在这里，我们提出了一个新的模型，在该模型中，巨噬细胞NOS3产生的NO对巨噬细胞的激活起到生理刹车的作用。在肥胖期间，我们认为巨噬细胞来源的NO的减少释放了这种刹车，增加了巨噬细胞的激活，促进了胰岛素抵抗。我们提出了一个新的假设，即巨噬细胞NOS3/NO需要通过其对巨噬细胞激活和骨髓生成的影响来维持肝脏的胰岛素敏感性，而这些作用的丧失会导致肥胖相关的肝脏胰岛素抵抗。如果这一假设是正确的，其翻译意义将是考虑在内的，因为已经有了不增加生物利用度的治疗选择。

 DESCRIPTION (provided by applicant): Obesity affects nearly half of the adult U.S. population and represents the single most important risk factor for development of insulin resistance and diabetes. Obesity is associated with a state of chronic, low-grade inflammation in insulin target-tissues such as the liver and adipose tissue. At the cellular level, macrophages appear to play a major role in promoting obesity-related inflammation. During the development of insulin resistance, resident liver macrophages (Kupffer cells) and monocytes that are recruited to the liver from the bone marrow (myelopoiesis) become activated, and release cytokines and chemokines. These molecules contribute to insulin resistance and to the development of type 2 diabetes (T2D). More importantly, abrogation of these macrophage-driven inflammatory mediators attenuates the development of insulin resistance/diabetes during obesity. Unfortunately, the factors that oppose these inflammatory macrophage-derived mediators have not been identified. Nitric oxide and endothelial nitric oxide synthase (eNOS or Nos3) are well-established contributors to vascular homeostasis. Nevertheless, loss of Nos3 appears to result in metabolic derangements that contribute to insulin resistance. More specifically, a reduction in Nos3-derived NO during obesity precedes the development of insulin resistance and genetic deletion of Nos3 (Nos3-/- mouse) is associated with both systemic and hepatic insulin resistance. Moreover, pharmacologic strategies that restore NO bioavailability during obesity (e.g. PDE5 inhibition) and genetic strategies that increase NO production (e.g. Nos3 overexpression) restore insulin sensitivity in mice. Our laboratory and others have long attributed the salutary metabolic effects of Nos3 to endothelium-mediated improvement of blood flow that increases delivery of nutrients to insulin-sensitive tissues such as liver, muscle, and adipose tissue, thereby facilitating nutrient utilization or storage and maintaining metabolic homeostasis. However, recent work from our laboratory suggests that, during obesity, macrophage Nos3-not endothelial Nos3-preserves metabolic homeostasis in a cell-autonomous manner by reducing macrophage production of inflammatory cyto/chemokines. Here we propose a novel model in which NO produced by macrophage Nos3 acts as a physiological brake on macrophage activation. During obesity, we propose that a reduction in macrophage-derived NO releases this brake, increasing macrophage activation and promoting insulin resistance. We propose the novel hypothesis that macrophage Nos3/NO is required to maintain hepatic insulin sensitivity through its effects on macrophage activation and myelopoiesis, and that the loss of these effects of NO leads to obesity-associated hepatic insulin resistance. If this hypothesis is correct, the translational significance will be considerale because therapeutic options that increase NO bioavailability are already available.