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: 10524769
• 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/10524769
• 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; 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; 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.

项目概要/摘要 2 型糖尿病 (T2DM) 的患病率在全球范围内急剧上升，目前已 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 大多数患者的 T2DM 控制不佳，导致大量发病率和死亡率。胰岛素抵抗是 T2DM 的主要病因。然而，没有直接改善胰岛素的临床选择 敏感性，但噻唑烷二酮除外，由于不良副作用而很少使用。 肥胖是胰岛素抵抗的最常见原因，越来越多的证据表明： 肥胖引起的炎症（或代谢炎症）是胰岛素抵抗和肥胖的重要原因 相关的代谢并发症。因此，预防方面存在巨大的未满足的医疗需求。 和治疗代谢炎症。然而，目前尚不清楚慢性代谢炎症是如何引发和 在肥胖的发展过程中传播，以及为什么它没有得到解决。巨噬细胞是主要的 免疫细胞类型介导代谢炎症，有证据表明巨噬细胞的变化 线粒体活性可以促进巨噬细胞的促炎激活和 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尚不清楚 明白了。我们将从一个新的角度解决肥胖引起的代谢炎症问题，重点关注 线粒体生物学具有新的目标和假设。我们初步认为 ANT2 是 巨噬细胞中 FFA 的线粒体传感器诱导线粒体重塑，有利于亲 炎症激活。由于肥胖症中血浆 FFA 增加的主要来源是脂肪细胞，因此 FFA- 诱导的 ANT2 激活可以提供脂肪组织特异性促炎巨噬细胞激活 肥胖的机制。有趣的是，巨噬细胞 ANT2 KO 的影响包括 线粒体数量、质量和容量，而脂肪细胞或肌细胞 ANT2 KO 不会导致 这些变化。这表明巨噬细胞 ANT2 通过细胞介导线粒体重塑 与脂肪细胞和肌细胞中的 ANT2 效应不同的类型特异性机制。我们将探索 巨噬细胞ANT2是否介导肥胖者代谢炎症的引发和/或维持 脂肪组织。然后我们将评估 ANT2 如何调节线粒体容量、动力学和 代谢支持巨噬细胞的促炎激活，以及巨噬细胞 ANT2 如何 激活会诱导胰岛素抵抗。如果成功的话，我们的研究将提供一种新的机制 肥胖会诱发组织选择性代谢炎症和胰岛素抵抗。圆满完成了 拟议的研究将确定 ANT2 作为预防代谢炎症的新疗法的潜在靶点， 胰岛素抵抗和葡萄糖不耐受。