ADIPOSE REMODELING & VASCULAR PHENOTYPES IN OBESITY

血管内皮功能是肥胖患者心血管风险的关键决定因素。我们最近发现促炎脂肪表型与胰岛素抵抗和血管功能障碍相关。 虽然共同的炎症机制是动脉粥样硬化和脂肪重塑的基础，但对脂肪炎症的不良血管后果或这种关系如何通过大规模体重减轻来调节知之甚少。在目标1中，我们提出了脂肪组织表型和脂肪中局部微血管功能之间的关系。在200名肥胖患者中，我们将在减肥手术期间对脂肪库进行活检，并通过使用免疫组织化学、流式细胞术和rt-PCR定量脂肪细胞因子表达、巨噬细胞密度、巨噬细胞极化（M1/M2）来评估脂肪库特异性炎症活性。这些发现将与从脂肪组织分离的小动脉的内皮血管舒张功能有关。我们假设，血管从更多的发炎脂肪将表现出促动脉粥样硬化的档案。在目标2中，我们将通过检查目标1中所有受试者在减肥手术前的肱动脉血流介导的扩张和反应性充血来确定脂肪中的微血管功能是否与全身血管功能相关。我们将把这些全身大血管和微血管功能的测量与脂肪组织中的血管表型和炎症联系起来。我们假设脂肪中的动脉功能障碍与全身血管损伤状态有关。在目标3中，我们建议确定减肥手术后广泛的体重减轻对脂肪表型和局部及全身血管功能的影响。我们将在减肥手术后3个月和1年对同样的200名受试者重复血管研究和皮下脂肪活检。我们假设，体重减轻将改善血管健康，减少炎症负荷将更密切地关系到动脉表型比体重减轻的幅度。在目前可获得的心血管数据非常有限的一组非常肥胖受试者（BMI S35 kg/m2）中，拟定的研究可能会产生关于肥胖诱导心血管疾病机制的新的重要信息。

Vascular endothelial function is a critical determinant of cardiovascular risk in obesity. We have recently shown that a proinflammatory fat phenotype is coupled with insulin resistance and vascular dysfunction. While shared inflammatory mechanisms underlie both atherosclerosis and adipose remodeling, little is known about the adverse vascular consequences of adipose inflammation or how this relationship is modulated by large-scale weight loss. In aim 1, we propose to characterize the relationship between adipose tissue phenotype and local microvascular function in fat. In 200 obese individuals, we will biopsy fat depots during bariatric surgery and assess depot-speciflc inflammatory activity by quantifying adipocytokine expression, macrophage density, macrophage polarization (M1/M2) using immunohistochemistry, flowcytometry, and rt-PCR. These findings will be related to endothelial vasodilator function of small arterioles isolated from adipose tissue. We hypothesize that blood vessels from more inflamed fat will exhibit a proatherogenic profile. In aim 2, we will determine whether microvascular function in fat correlates with systemic vascular function by examining brachial artery flow-mediated dilation and reactive hyperemia prior to bariatric surgery in all subjects from aim 1. We will relate these measures of systemic macro- and microvascular function to vascular phenotype and inflammation in adipose tissue. We hypothesize that arterial dysfunction in fat will be associated with a generalized systemic state of vascular impairment. In aim 3, we propose to determine the effects of extensive weight loss following bariatric surgery on adipose phenotype and local and systemic vascular function. We will repeat vascular studies and biopsy subcutaneous fat at 3 months and 1-year after bariatric surgery in the same 200 subjects. We hypothesize that weight reduction will improve vascular health and that reduced inflammatory burden will relate more closely to arterial phenotype than the magnitude of weight loss. The proposed studies are likely to yield novel and important information about the mechanisms of obesity-induced cardiovascular disease in a group of very obese subjects (BMI S35 kg/m2) where very limited cardiovascular data are currently available.