Adipose inflammation, mitochondrial function & endothelial phenotypes in obesity

脂肪炎症、线粒体功能

• 批准号: 8689153
• 负责人: NOYAN GOKCE
• 金额: $ 45.59万
• 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/8689153
• 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.

描述(申请人提供)：我们实验室发表的工作表明，脂肪组织炎症是肥胖受试者代谢应激和血管内皮功能障碍的关键病理过程，支持脂肪质量和数量与全身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，脂肪微血管的血管生成和血管扩张功能受损与促炎和缺氧性脂肪表型密切相关。由于脂肪释放的脂肪细胞因子改变了血管线粒体的功能，增加了活性氧(ROS)并损害了内皮一氧化氮的生物活性，我们将检查炎症和线粒体功能障碍作为与脂肪血管轮廓受损相关的机制的重要性。在目标1中，我们将在减肥手术期间对150名肥胖者的脂肪库进行活组织检查，并根据临床表型来表征脂肪炎症与脂肪库特异性血管生成能力和血管的关系。我们假设脂肪炎症将与毛细血管稀疏和血管生成障碍有关。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来表征线粒体的形态、ROS的产生和基因的表达。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扩张作用来补充这些分析。我们假设线粒体功能障碍与内皮依赖性血管扩张和血管生成受损有关。在目标3中，我们将在相同的150名受试者中，在减肥手术后1个月和12个月重复目标1和2中描述的脂肪和血管研究，以研究减肥手术后广泛减肥的效果。我们将寻求确定脂肪内内皮特异性功能的代谢、线粒体和/或炎症决定因素与体重减轻的早期和晚期相关。拟议的研究旨在提供关于肥胖引起的心脏代谢性疾病的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，目前临床数据很少。