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Nos 3）是公认的贡献者 血管内环境的平衡然而，Nos 3的缺失似乎会导致代谢紊乱， 导致胰岛素抵抗。更具体地说，肥胖期间Nos 3衍生的NO减少 在胰岛素抵抗的发展之前4和Nos 3的遗传缺失（Nos 3-/-小鼠）是 与全身和肝脏胰岛素抵抗相关。此外， 在肥胖期间恢复NO生物利用度（例如，PDE 5抑制）和增加NO的遗传策略 在小鼠中，胰岛素生产（例如Nos 3过表达）恢复胰岛素敏感性。 我们的实验室和其他实验室长期以来一直将Nos 3的有益代谢作用归因于 内皮介导的血流改善，增加向胰岛素敏感性 组织如肝脏、肌肉和脂肪组织，从而促进营养利用或储存， 维持代谢平衡然而，我们实验室最近的工作表明， 在肥胖症中，骨髓来源的细胞Nos 3-而不是内皮Nos 3-保持代谢稳态。 在这里，我们提出了一种新的模型，其中由红细胞（RBC）Nos 3产生的NO作为一种新的细胞因子。 对炎症激活的生理制动。在肥胖期间，我们建议减少红细胞- 衍生的NO释放该制动器，增加肝巨噬细胞活化并促进胰岛素分泌。 阻力 红细胞和巨噬细胞之间的串扰对于红细胞清除至关重要， 巨噬细胞仔细检查通过的红细胞，清除肝脏和脾脏中受损的红细胞， 表明RBC参与巨噬细胞介导的对病原体的免疫应答。这些 这些观察建立了RBC和免疫细胞之间重要但研究不足的相互作用。 我们提出了新的假说，即红细胞Nos 3/NO是维持肝脏胰岛素所必需的 敏感性通过其影响，以限制激活库普弗细胞，并认为这些影响的损失， 导致肥胖相关的肝脏胰岛素抵抗。如果这一假设是正确的， 重要性是相当大的，因为增加NO生物利用度的治疗选择 已经有了。这些疗法可能会预防肥胖介导的胰岛素抵抗。此外，委员会认为， 本文提出的研究可能揭示了一种新的红细胞依赖性途径， 在轻度慢性炎症状态如肥胖或动脉粥样硬化中激活。我们提出 目标：目标1。为了检验RBC Nos 3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激活来增强对高敏感性的敏感性。目标2.为了确定T2 D是否 与红细胞NO含量降低和红细胞脱氢酶1活性增加有关。

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.