权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
10181020
负责人：
Francis Kim
金额：
$ 56.38万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-20 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10181020
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 genetic approach improved insulin sensitivity macrophage metabolomics novel obesity development obesity prevention overexpression pathogen preservation

项目摘要

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）是公认的贡献者达到血管稳态。然而，Nos3 的缺失似乎会导致代谢紊乱，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4的发展，并且Nos3基因缺失（Nos3–/–小鼠）是与全身和肝脏胰岛素抵抗有关。此外，药物策略恢复肥胖期间 NO 的生物利用度（例如 PDE5 抑制）和增加 NO 的遗传策略产生（例如Nos3过度表达）恢复小鼠的胰岛素敏感性。我们的实验室和其他人长期以来将 Nos3 的有益代谢作用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肝脏、肌肉和脂肪组织等组织，从而促进营养物质的利用或储存和维持代谢稳态。然而，我们实验室最近的工作表明，在肥胖时，骨髓来源的 Nos3 细胞（而非内皮 Nos3）可以保持代谢稳态。在这里，我们提出了一种新模型，其中红细胞 (RBC) Nos3 产生的 NO 作为对炎症激活的生理制动。在肥胖期间，我们建议减少红细胞- 衍生的一氧化氮释放这种制动，增加肝巨噬细胞的活化并促进胰岛素的产生反抗。红细胞和巨噬细胞之间的串扰对于红细胞清除至关重要，因为住宅巨噬细胞仔细检查通过的红细胞并清除肝脏和脾脏中受损的红细胞，并且还发挥作用表明红细胞参与巨噬细胞介导的针对病原体的免疫反应。这些观察结果表明红细胞和免疫细胞之间存在重要但尚未充分研究的相互作用。我们提出新的假设：RBC Nos3/NO 是维持肝胰岛素所必需的通过其限制库普弗细胞活化的作用来敏感性，并且NO的这些作用的丧失导致肥胖相关的肝脏胰岛素抵抗。如果这个假设是正确的，那么翻译意义将是相当大的，因为增加 NO 生物利用度的治疗选择是已经可用。这些疗法可能会预防肥胖介导的胰岛素抵抗。此外，这里提出的研究可能会揭示一种新的红细胞依赖性衰减巨噬细胞途径在肥胖或动脉粥样硬化等低度慢性炎症状态下激活。我们建议目标如下：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弗细胞的激活来提高敏感性。目标 2. 确定是否为 T2D 与红细胞 NO 含量减少和精氨酸酶 1 活性增加有关。