Adipose inflammation, mitochondrial function & endothelial phenotypes in obesity

脂肪炎症、线粒体功能

• 批准号: 8340493
• 负责人: NOYAN GOKCE
• 金额: $ 46.52万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-05 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8340493
• 关键词: Adipose tissue; Adult; American; American Heart Association; Area; Bariatrics; Biological Assay; Biology; Biopsy; Blood Vessels; Blood capillaries; Body Weight decreased; Body mass index; Brain Hypoxia-Ischemia; Cardiovascular Diseases; Cardiovascular system; Categories; Cause of Death; Cessation of life; Clinical Data; Complement; Data; Disease; Endothelial Cells; Endothelium; Exhibits; Fatty acid glycerol esters; Gene Expression; Genes; Healthcare; Human; Hypoxia; Immunohistochemistry; Individual; Inflammation; Inflammatory; Intervention; Laboratories; Life; Link; Metabolic; Metabolic stress; Methods; Mitochondria; Morbid Obesity; Morphology; Myocardial Ischemia; Nitric Oxide; Obesity; Obesity associated cardiovascular disease; Operative Surgical Procedures; Overweight; Pathologic Processes; Phenotype; Play; Population; Positioning Attribute; Prevalence; Process; Production; Publishing; Reactive Oxygen Species; Research Priority; Risk Factors; Role; Shapes; Staging; Stroke; Systemic disease; Tissues; Up-Regulation; Vascular Diseases; Vascularization; Vasodilation; Vasodilator Agents; Vasomotor; Video Microscopy; Visceral; Weight; Work; adipokines; angiogenesis; bariatric surgery; capillary; care burden; clinical phenotype; clinically relevant; combat; cost; cytokine; density; effective therapy; fluorescence imaging; matrigel; mitochondrial dysfunction; multidisciplinary; novel; premature; response; social; subcutaneous; vascular endothelial dysfunction

DESCRIPTION (provided by applicant): Published work from our laboratory shows that adipose tissue inflammation is a key pathological process linked to metabolic stress and vascular endothelial dysfunction in obese subjects, supporting the growing paradigm that both quality and quantity of fat are germane to systemic disease processes. Our preliminary data demonstrate that impaired angiogenic and vasodilator functions of the adipose microvasculature are closely linked to proinflammatory and hypoxic adipose phenotypes. As adipocytokines released from fat alter vascular mitochondrial function in a manner that increases reactive oxygen species (ROS) and impairs endothelial nitric oxide bioaction, we will examine the importance of inflammation and mitochondrial dysfunction as interrelated mechanisms linked to impaired adipose vascular profiles. In aim 1, in 150 obese individuals we will biopsy fat depots during bariatric surgery and characterize the relation between adipose inflammation and depot-specific angiogenic capacity and vascularity in relation to clinical phenotypes. We hypothesize that adipose inflammation will be associated with capillary rarefaction and impaired angiogenesis. In aim 2, we will isolate endothelial cells from the adipose tissue of each subject from aim 1 and characterize mitochondrial morphology, ROS production, and gene expression using fluorescence imaging and quantitative PCR. We will complement these analyses by studying vasodilation of adipose microvessels by videomicroscopy in response to mitochondrial modulators. We hypothesize that mitochondrial dysfunction will be linked to impaired endothelium-dependent vasodilation and angiogenesis. In aim 3, we will study the effects of extensive weight loss following bariatric surgery by repeating the adipose and vascular studies described in aims 1 and 2, at 1- and 12-months after bariatric surgery in the same 150 subjects. We will seek to identify metabolic, mitochondrial, and/or inflammatory determinants of endothelium-specific functions within fat in association with both early and late stages of weight decrease. The proposed studies are positioned to yield novel information about mechanisms of obesity- induced cardiometabolic disease and the effects of bariatric weight loss on vascular biology in a group of severely obese subjects (BMI e35 kg/m2) where very few clinical data are currently available. PUBLIC HEALTH RELEVANCE: Obesity has emerged as the most critical health care problem in the US. Currently over 65% of adults in the US are overweight and the prevalence of severe obesity has more than tripled in the last decade with no signs of slowing. Cardiovascular disease is the main cause of death in this population and this project seeks to investigate mechanisms of obesity-related vascular disease as an area of high priority research.

描述（由申请人提供）：我们实验室发表的研究表明，脂肪组织炎症是与肥胖受试者的代谢应激和血管内皮功能障碍相关的关键病理过程，支持脂肪的质量和数量与全身性疾病过程密切相关的日益增长的范式。我们的初步数据表明，受损的血管生成和血管扩张功能的脂肪微血管是密切相关的促炎症和缺氧脂肪表型。由于脂肪释放的脂肪细胞因子以增加活性氧（ROS）和损害内皮一氧化氮生物作用的方式改变血管线粒体功能，我们将研究炎症和线粒体功能障碍作为与受损脂肪血管特征相关的相关机制的重要性。在目标1中，我们将在减肥手术期间对150名肥胖个体的脂肪库进行活检，并描述脂肪炎症与脂肪库特异性血管生成能力和与临床表型相关的血管分布之间的关系。我们推测脂肪炎症与毛细血管稀疏和血管生成受损有关。在目标2中，我们将从目标1的每个受试者的脂肪组织中分离内皮细胞，并使用荧光成像和定量PCR表征线粒体形态、ROS产生和基因表达。我们将通过视频显微镜研究线粒体调节剂对脂肪微血管的舒张作用来补充这些分析。我们推测线粒体功能障碍与内皮依赖性血管舒张和血管生成受损有关。在目标3中，我们将通过在相同的150名受试者中重复目标1和2中描述的脂肪和血管研究，在减肥手术后1个月和12个月研究减肥手术后广泛减肥的影响。我们将寻求确定与体重减轻的早期和晚期相关的脂肪内内皮特异性功能的代谢、线粒体和/或炎症决定因素。拟定的研究旨在产生关于肥胖诱导的心脏代谢疾病机制以及减肥对一组严重肥胖受试者（BMI e35 kg/m2）血管生物学影响的新信息，目前这些受试者的临床数据非常少。 公共卫生相关性：肥胖已成为美国最严重的卫生保健问题。目前，美国超过65%的成年人超重，严重肥胖的患病率在过去十年中增加了两倍多，而且没有放缓的迹象。心血管疾病是这一人群的主要死因，本项目旨在研究肥胖相关血管疾病的机制，并将其作为一个高度优先研究领域。