Red Blood Cell Endothelial Nitric Oxide Attenuates Insulin Resistance

红细胞内皮一氧化氮减弱胰岛素抵抗

• 批准号: 9767272
• 负责人: Francis Kim
• 金额: $ 56.37万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-20 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9767272
• 关键词: Adipose tissue; Adult; Affect; Age; Arginine; Atherosclerosis; Attenuated; Biological Availability; Blood Vessels; Blood flow; Bone Marrow; Cells; Chronic; Clinical Research; Data; Development; Diabetes Mellitus; Disease; Endothelial Cells; Endothelium; Erythrocytes; Erythroid; Erythropoietin Receptor; Fatty acid glycerol esters; Genetic; Genetic Models; Hepatic; Homeostasis; Immune; Immune response; Inflammation; Inflammation Mediators; Inflammatory; Insulin; Insulin Resistance; Knock-out; Kupffer Cells; Laboratories; Liver; Macrophage Activation; Mediating; Mediator of activation protein; Metabolic; Modeling; Mus; Muscle; NOS3 gene; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Pathway interactions; Patients; Pharmacology; Physiological; Play; Population; Production; Risk Factors; Role; Source; Spleen; Testing; Therapeutic; Tissues; United States; Work; arginase; endothelial dysfunction; feeding; improved; insulin sensitivity; macrophage; metabolomics; novel; obesity development; overexpression; pathogen; preservation; prevent

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.

一氧化氮和内皮一氧化氮合酶（ENOS或NOS3）是公认的贡献者 进行血管稳态。然而，NOS3的损失似乎导致代谢发展 有助于胰岛素抵抗。更具体地说，肥胖期间NOS3衍生的NO减少 先于胰岛素抵抗的发展和NOS3（NOS3 - / - 小鼠）的遗传缺失是 与系统性和肝胰岛素抵抗相关。此外，药物研究 在肥胖期间没有恢复生物利用度（例如PDE5抑制）和遗传策略，而遗传策略不增加 产生（例如NOS3过表达）恢复了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的代谢作用归因于 内皮介导的血流改善，从而增加了营养成分向胰岛素敏感的递送 组织，例如肝脏，肌肉和脂肪组织，从而支持营养利用或储存以及 维持代谢稳态。但是，我们实验室的最新工作表明，在 肥胖，骨髓衍生的细胞NOS3-不可以内皮的NOS3 - 代谢稳态。 在这里，我们提出了一个新型模型，其中没有红细胞（RBC）NOS3产生的新模型充当 炎症激活的生理制动。在肥胖期间，我们提出减少RBC- 衍生不释放该制动，增加了肝巨噬细胞激活并促进胰岛素 反抗。 RBC和巨噬细胞之间的串扰对于RBC清除至关重要，因为居民 巨噬细胞仔细检查通过RBC并清除肝脏和脾脏中受损的RBC，还可以工作 提示RBC参与巨噬细胞介导的对病原体的免疫血液的参与。这些 观察结果确定了RBC和免疫细胞之间重要但不足的相互作用。 我们提出了一种新的假设，即需要RBC NOS3/NO维持肝胰岛素需要 通过其影响限制库普弗细胞激活的敏感性，而这些效果的丧失no 导致肥胖相关的肝胰岛素抵抗。如果这个假设正确，则翻译 意义将是相当大的，因为没有生物利用度的治疗选择是 已经可用。这些疗法可能会阻止肥胖介导的胰岛素抵抗。此外， 这里提出的研究可能会发现一种新型的RBC依赖性途径来减轻巨噬细胞 低度慢性炎症状态（例如肥胖或动脉粥样硬化）的激活。我们建议 以下目的：目标1。检验RBC NOS3足以维持肝胰岛素的假设 通过减弱肥胖期间库普夫细胞激活的敏感性。目标2。确定T2D是否是 与降低的RBC无含量和精氨酸酶1活性相关。