Red Blood Cell Endothelial Nitric Oxide Attenuates Insulin Resistance

一氧化氮和内皮型一氧化氮合酶(eNOS或NOS3)是公认的贡献者 血管内环境的稳定。然而，NOS3的缺失似乎会导致代谢紊乱， 会导致胰岛素抵抗。更具体地说，肥胖期间NOS3衍生的NO减少 在发生胰岛素抵抗和NOS3基因缺失之前(NOS3-/-小鼠)是 与全身和肝脏的胰岛素抵抗有关。此外，药理学策略 在肥胖期间恢复NO的生物利用度(例如，抑制PDE5)和增加NO的遗传策略 生产(例如，NOS3过表达)可恢复小鼠的胰岛素敏感性。 我们的实验室和其他实验室长期以来一直将NOS3的有益代谢效应归因于 内皮介导的血流改善，增加对胰岛素敏感的营养物质的输送 组织，如肝脏、肌肉和脂肪组织，从而促进营养利用或储存和 维持代谢动态平衡。然而，我们实验室最近的研究表明，在 肥胖，骨髓来源的细胞NOS3-而不是内皮细胞NOS3-维持代谢动态平衡。 在这里，我们提出了一个新的模型，其中由红细胞(RBC)NOS3产生的NO作为一种 对炎症激活的生理刹车。在肥胖期间，我们建议红细胞减少- 衍生的一氧化氮释放这种刹车，增加肝脏巨噬细胞的激活并促进胰岛素 抵抗。 RBC和巨噬细胞之间的串扰对RBC清除至关重要，因为 巨噬细胞仔细观察通过的红细胞，并移除肝和脾中受损的红细胞，还工作 提示红细胞参与巨噬细胞介导的对病原体的免疫反应。这些 观察确定了红细胞和免疫细胞之间重要但尚未被研究的相互作用。 我们提出了新的假设，即RBC NOS3/NO是维持肝脏胰岛素所必需的 通过其作用来限制库普弗细胞的激活的敏感性，以及这些作用的丧失 导致肥胖相关的肝脏胰岛素抵抗。如果这一假设是正确的，翻译过来的 意义将是相当大的，因为增加无生物利用度的治疗方案是 已经有货了。这些疗法可能会预防肥胖引发的胰岛素抵抗。此外， 这里提出的研究可能揭示一种新的红细胞依赖的途径来减弱巨噬细胞 在轻度慢性炎症状态下的激活，如肥胖或动脉粥样硬化。我们建议 目的：1.检验RBC NOS3足以维持肝脏胰岛素的假设 通过减弱肥胖期间库普弗细胞的激活来提高敏感性。目的2.确定T2D是否 与红细胞NO含量降低和精氨酸酶1活性升高有关。

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 resistance4 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, bone marrow derived cell Nos3—not endothelial Nos3—preserves metabolic homeostasis. Here we propose a novel model in which NO produced by red blood cell (RBC) Nos3 acts as a physiological brake on inflammatory activation. During obesity, we propose that a reduction in RBC- derived NO releases this brake, increasing hepatic macrophage activation and promoting insulin resistance. Crosstalk between RBC and macrophage are crucial for RBC clearance, since residential macrophages scrutinize passing RBC and remove damaged RBC in the liver and spleen and work also suggests that RBC participate in macrophage-mediated immune responses to pathogens. These observations establish an important yet under-investigated interaction between RBC and immune cells. We propose the novel hypothesis that RBC Nos3/NO is required to maintain hepatic insulin sensitivity through its effects to limit activation of Kupffer cells, 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 considerable because therapeutic options that increase NO bioavailability are already available. These therapies might prevent obesity-mediated insulin resistance. Furthermore, studies proposed here may uncover a novel RBC dependent pathway for attenuating macrophage activation in states of low-grade chronic inflammation such as obesity or atherosclerosis. We propose the following aims: Aim 1. To test the hypothesis that RBC Nos3 is sufficient to maintain hepatic insulin sensitivity by attenuating Kupffer cell activation during obesity. Aim 2. To determine whether T2D is associated with reduced RBC NO content and increased arginase 1 activity.