Adipose inflammation, mitochondrial function & endothelial phenotypes in obesity

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代谢应激和血管内皮功能障碍相关的关键病理过程，支持了脂肪质量和数量与全身性疾病过程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脂肪表型密切相关。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脂肪血管受损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名肥胖个体进行脂肪库活检，并表征脂肪炎症与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。我们假设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中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脂肪微血管在线粒体调节剂作用下的血管舒张来补充这些分析。我们假设线粒体功能障碍将与内皮依赖性血管舒张和血管生成受损有关。在目标3中，我们将通过重复目标1和目标2中描述的脂肪和血管研究，在相同的150名受试者中，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效果。我们将寻找脂肪中内皮特异性功能的代谢、线粒体和/或炎症决定因素，这些决定因素与体重减轻的早期和晚期有关。拟议的研究旨在获得关于肥胖诱导的心脏代谢疾病机制的新信息，以及在一组严重肥胖受试者（BMI为35 kg/m2）中体重减轻对血管生物学的影响，目前很少有临床数据可用。

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.