Anti-Angiogenic Mechanisms in Human Obesity

描述(由申请者提供)：肥胖已成为美国最严重的医疗保健问题之一，目前69%的美国人口超重或肥胖。脂肪组织功能障碍是将肥胖与心脏代谢性疾病发病机制联系起来的一个重要标志，我们小组之前的工作已经证明，脂肪组织的质量特性决定了系统的表型。特别是，肥胖时脂肪组织血管生成受损与炎症和代谢功能障碍有关；然而，致病机制尚不完全清楚。我们描述了一种新的内源性血管内皮生长因子(VEGF-A)亚型，VEGF-A165b，它在肥胖中选择性过度表达，并抑制血管生成。我们的初步数据表明，在肥胖条件下，WNT5a信号系统的扰动上调了血管内皮生长因子-A165b的表达，而减肥手术减轻了肥胖的影响。在目标1中，我们将在150名肥胖者和50名瘦身受试者的脂肪活检样本中检测脂肪库特异性微血管生成反应。我们将研究血管内皮生长因子-A亚型与血管生成能力和血管形成的关系。我们推测，抑制亚型血管内皮生长因子-A165b在肥胖中上调，与脂肪中的抗血管生成作用相关，并与全身代谢功能障碍有关。在目标2中，将使用从目标1获得的人类脂肪组织样本来使用Wnt信号的特异性抑制剂，以提供一个分子框架来了解血管内皮生长因子-A 165b的表达调控。在目标3中，我们将在减肥手术后6个月重新检测与目标1相同的150名肥胖者的脂肪血管生成能力和血管内皮生长因子亚型的表达。我们将测试目标2中明确的相关分子通路是否受体重减轻的影响。我们试图确定与代谢变化相关的脂肪组织生物学和血管生成的新决定因素，这些变化将与肥胖者显著的体重减轻相关。我们的建议可能确定Wnt5a-VEGF-A165b轴是一种新的血管生成、脂肪组织生物学调节因子，从而可能导致临床肥胖症的系统性疾病，并可能导致新的治疗靶点的确定。

DESCRIPTION (provided by applicant): Obesity has emerged as one of the most critical health care problems in the US as 69% of the US population is currently overweight or obese. Adipose tissue dysfunction is an essential hallmark linking obesity to the pathogenesis of cardiometabolic disease, and prior work form our group has demonstrated that qualitative properties of adipose tissue shape systemic phenotypes. In particular, impaired adipose tissue angiogenesis in obesity has been associated with inflammation and metabolic dysfunction; however pathogenic mechanisms are incompletely understood. We describe a novel endogenous isoform of vascular endothelial growth factor (VEGF-A), VEGF-A165b that is selectively over-expressed in obesity and inhibits angiogenesis. Our preliminary data suggest that perturbations in the Wnt5a signaling system up-regulates VEGF-A165b under conditions of obesity that is modified by bariatric surgical weight loss. In aim 1, we will examine adipose depot-specific microvascular angiogenic responses in biopsied fat samples from 150 obese and 50 lean subjects. We will characterize VEGF-A isoforms in relation to angiogenic capacity and vascularization. We hypothesize that inhibitory isoform VEGF-A165b will be up- regulated in obesity, associated with anti-angiogenic actions in fat, and relate to whole body metabolic dysfunction. In aim 2, specific inhibitors of Wnt signaling will be employed using human adipose tissue samples secured from aim 1 to provide a molecular framework for understanding the regulation of VEGF-A 165b expression. In aim 3, we will re-examine adipose angiogenic capacity and VEGF isoform expression at 6 months following bariatric surgery in the same 150 obese subjects from aim 1. We will test whether relevant molecular pathways specifically identified in aim 2 are influenced by weight reduction. We seek to identify novel determinants of adipose tissue biology and angiogenesis in relation to metabolic changes which will develop in association with marked weight loss in obese individuals. Our proposal may identify the Wnt5a-VEGF-A 165b axis as a novel modulator of angiogenesis, adipose tissue biology, and consequently, systemic disease in clinical obesity and potentially lead to the identification of new therapeutic targets.