ANT2 in metaflammation and insulin resistance

ANT2 在代谢炎症和胰岛素抵抗中的作用

• 批准号: 10319611
• 负责人: Yun Sok Lee
• 金额: $ 39.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-16 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10319611
• 关键词: Adenine Nucleotide Translocase; Adipocytes; Adipose tissue; Anti-Inflammatory Agents; Antidiabetic Drugs; Automobile Driving; Biology; Chronic; Clinical; Cues; Data; Diabetes Mellitus; Electron Transport; Epidemic; Etiology; Exhibits; Fatty Liver; Functional disorder; Gene Expression; Glucose Intolerance; Glucose Metabolism Disorders; Growth; Hepatocyte; Immune; Inflammation; Inflammatory; Inner mitochondrial membrane; Insulin Resistance; Knock-out; Knockout Mice; Macrophage Activation; Maintenance; Measures; Mediating; Medical; Membrane Proteins; Metabolic; Metabolism; MicroRNAs; Mitochondria; Mitochondrial Proteins; Molecular; Morbidity - disease rate; Muscle Cells; Myelogenous; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nutritional; Obese Mice; Obesity; Patients; Phagocytosis; Phenotype; Plasma; Play; Prevalence; Prevention; Process; Production; Reactive Oxygen Species; Regulation; Reporting; Respiration; Role; Signal Transduction; Source; System; Testing; Therapeutic; Thiazolidinediones; Tissues; cell type; exosome; extracellular; flexibility; improved; insulin sensitivity; insulin signaling; macrophage; mitochondrial dysfunction; monocyte; mortality; mouse development; new therapeutic target; nonalcoholic steatohepatitis; novel; obesity development; prevent; response; sensor; side effect; trafficking

PROJECT SUMMARY/ABSTRACT The prevalence of Type 2 diabetes mellitus (T2DM) is rising dramatically on a global basis and has now reached epidemic proportions. Current anti-diabetic therapeutics are available, but are inadequate to fully control T2DM in most patients, resulting in a great deal of morbidity and mortality. Insulin resistance is a major etiologic cause underlying T2DM. However, there are no clinical options to directly improve insulin sensitivity, except for thiazolidinediones, which are infrequently used due to unwanted side effects. Obesity is the most common cause of insulin resistance, and accumulating evidence indicates that obesity-induced inflammation (or metaflammation) is an important cause of insulin resistance and obesity- associated metabolic complications. Therefore, there are huge unmet medical needs for the prevention and treatment of metaflammation. However, it is not known how chronic metaflammation is initiated and propagates during the development of obesity, and why it is not resolved. Macrophages are the major immune cell type mediating metaflammation, and evidence suggest that changes in macrophage mitochondria activity can promote pro-inflammatory activation and M1-like polarization of macrophages. However, how mitochondrial activity is regulated during the course of M1- or M2-like macrophage polarization, especially in the obese/energy-excess adipose tissue microenvironment is not clearly understood. We will tackle the question of obesity-induced metaflammation from a new angle, focusing on mitochondrial biology with a novel target and hypothesis. Our preliminary suggest that ANT2 is a mitochondrial sensor of FFAs in macrophages to induces mitochondria remodeling favoring pro- inflammatory activation. Since the major source of increased plasma FFAs in obesity is adipocytes, FFA- induced ANT2 activation can provide an adipose tissue-specific pro-inflammatory macrophage activation mechanism in obesity. Interestingly, the effect of macrophage ANT2 KO includes the changes in mitochondrial number, mass, and capacity, whereas adipocyte or myocyte ANT2 KO does not cause these changes. This suggest that macrophage ANT2 mediates mitochondria remodeling through a cell type-specific mechanism that is distinct from ANT2 effects in adipocytes and myocytes. We will explore whether macrophage ANT2 mediates the initiation and/or maintenance of metaflammation in obese adipose tissue. We will then assess how ANT2 regulates mitochondrial capacity, dynamics, and metabolism to support the pro-inflammatory activation of macrophages, and how macrophage ANT2 activation induces insulin resistance. If successful, our studies will provide a novel mechanism for how obesity induces tissue-selective metaflammation and insulin resistance. Successful completion of the proposed study will identify ANT2 as a potential target for novel therapeutics to prevent metaflammation, insulin resistance, and glucose intolerance.

项目总结/摘要 2型糖尿病（T2 DM）的患病率在全球范围内急剧上升， 达到了流行病的程度。目前的抗糖尿病疗法是可用的，但不足以完全治疗糖尿病。 控制T2 DM的大部分患者，导致大量的发病率和死亡率。胰岛素抵抗是 T2 DM的主要病因。然而，目前还没有直接改善胰岛素的临床选择 敏感性，除了噻唑烷二酮类，由于不希望的副作用而很少使用。 肥胖是胰岛素抵抗最常见的原因，越来越多的证据表明， 肥胖引起的炎症（或metaflammation）是胰岛素抵抗和肥胖的重要原因- 相关的代谢并发症。因此，在预防方面存在巨大的未满足的医疗需求。 和治疗后炎症。然而，尚不清楚慢性炎症是如何开始的， 在肥胖症的发展过程中传播，以及为什么它没有得到解决。宏观经济是主要的 免疫细胞类型介导的炎症反应，证据表明巨噬细胞的变化 线粒体活性可促进巨噬细胞的促炎活化和M1样极化。 然而，在M1或M2样巨噬细胞的过程中，线粒体活性是如何调节的， 极化，特别是在肥胖/能量过剩的脂肪组织微环境中， 明白我们将从一个新的角度来解决肥胖引起的炎症反应问题，重点是 线粒体生物学与新的目标和假设。我们初步认为ANT 2是一种 巨噬细胞中FFA的线粒体传感器诱导线粒体重塑， 炎症激活由于肥胖症患者血浆FFA增加的主要来源是脂肪细胞，因此FFA- 诱导的ANT 2活化可提供脂肪组织特异性促炎巨噬细胞活化 肥胖的机制有趣的是，巨噬细胞ANT 2 KO的作用包括以下变化： 线粒体数量、质量和容量，而脂肪细胞或肌细胞ANT 2 KO不引起 这些变化。这表明巨噬细胞ANT 2通过细胞介导线粒体重塑 类型特异性机制，不同于脂肪细胞和肌细胞中的ANT 2作用。我们将探讨 巨噬细胞ANT 2是否介导肥胖大鼠中炎症反应的启动和/或维持 脂肪组织然后，我们将评估ANT 2如何调节线粒体的能力，动力学， 代谢支持巨噬细胞的促炎激活，以及巨噬细胞ANT 2 活化诱导胰岛素抗性。如果成功，我们的研究将提供一种新的机制， 肥胖诱导组织选择性炎症和胰岛素抵抗。成功完成 所提出的研究将鉴定ANT 2作为预防炎症转移的新疗法的潜在靶点， 胰岛素抵抗和葡萄糖耐受不良。