Angiotensin II Receptor Blockade and Adipose Tissue Inflammation in Obesity

描述（由申请人提供）：超重和肥胖，困扰着约65%的美国人口和全球超过10亿人，增加了患高血压的风险。肾素血管紧张素系统（RAS）的激活是肥胖导致高血压的重要机制。除了血管收缩和钠潴留作用外，血管紧张素II还具有强大的促炎作用，包括巨噬细胞浸润和促炎细胞因子在靶组织中的表达。脂肪组织似乎是产生促炎细胞因子（称为“脂肪因子”）的关键部位，包括肿瘤坏死因子-1 （TNF-1）、白细胞介素-6 （IL-6）和单核细胞趋化蛋白-1 （MCP-1）。虽然血管紧张素II受体阻断可以减少许多组织的炎症，但对人体脂肪组织的影响尚不清楚。重要的是，伴随肥胖的慢性低级别炎症状态通过促进胰岛素抵抗和加速心血管疾病而使高血压复杂化。因此，本研究的总体目标是确定血管紧张素II受体阻断对肥胖高血压患者脂肪组织炎症的影响。最近的临床试验结果表明，血管紧张素II受体阻断可减少2型糖尿病的发病。此外，肥胖高血压患者的特点是胰岛素抵抗，发展为2型糖尿病的风险较高。因此，第二个目的将是探讨脂肪组织巨噬细胞浸润和脂肪因子表达的变化与血管紧张素II受体阻断和胰岛素敏感性改善之间的关系。为了实现这些目标，44名肥胖（BMI为30 kg/m2）高血压（BP为收缩压140和/或舒张压90）患者（年龄为50-65岁）将被随机分配到8周的血管紧张素II受体拮抗剂奥美沙坦-美多地尔或安慰剂组。将进行皮下脂肪组织活检，并在基线和干预后8周评估胰岛素敏感性（静脉葡萄糖耐量试验）。分别通过免疫组织化学、RT-PCR和western blotting检测脂肪组织巨噬细胞浸润脂肪因子的表达。拟议的研究应该为未来的RO1提案提供有价值的初步数据，这些提案涉及的转化研究侧重于确定血管紧张素II受体阻断是否以及如何减少肥胖患者的脂肪组织炎症。最终，这些研究可能会改善临床对脂肪组织炎症的认识，进而改善这些个体的治疗和结果。本提案的主要目的是确定用于降低血压的特定药物是否也可以减少肥胖高血压患者脂肪组织中的炎症。所提出的研究结果可能最终导致改善临床对肥胖个体脂肪组织炎症的认识。重要的是，这些发现可能导致治疗脂肪组织炎症的特定靶点，脂肪组织炎症是与许多肥胖相关并发症相关的因素，进而改善肥胖个体的预后。

DESCRIPTION (provided by applicant): Overweight and obesity, which afflicts ~65% of the U.S. population and more than 1 billion people worldwide, increases the risk of developing hypertension. Activation of the renin angiotensin system (RAS) is an important mechanism by which obesity leads to hypertension. In addition to its vasoconstricting and sodium retaining actions, angiotensin II also has potent pro-inflammatory actions including macrophage infiltration and expression of proinflammatory cytokines in target tissues. Adipose tissue appears to be a key site for the generation of proinflammatory cytokines (termed `adipokines'), including tumor necrosis factor-1 (TNF-1), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1). Although angiotensin II receptor blockade reduces inflammation in many tissues, the effects on adipose tissue in humans are not clear. Importantly, the chronic low grade inflammatory state that accompanies obesity complicates hypertension by contributing to insulin resistance and accelerating cardiovascular disease. Therefore, the general aim of the present proposal will be to determine the influence of angiotensin II receptor blockade on adipose tissue inflammation in obese hypertensive humans. The results of recent clinical trials showed that angiotensin II receptor blockade reduces the onset of type 2 diabetes. In addition, obese hypertensives are characterized by insulin resistance and are at elevated risk of developing type 2 diabetes. Thus, a secondary aim will be to explore the relations among changes in adipose tissue macrophage infiltration and adipokine expression with angiotensin II receptor blockade and improvements in insulin sensitivity. To address these aims, 44 obese (BMI>30 kg/m2) hypertensive (BP>140 systolic and/or 90 diastolic) individuals (age=50-65 years) will be randomized to 8 weeks of either the angiotensin II receptor antagonist, olmesartan medoxidil, or placebo. Subcutaneous adipose tissue biopsies will be obtained and insulin sensitivity (intravenous glucose tolerance tests) will be assessed at baseline and following 8 weeks of the intervention. Adipose tissue macrophage infiltration adipokine expression will be quantified via immunohistochemistry and RT-PCR and western blotting, respectively. The proposed studies should provide valuable preliminary data for future RO1 proposals involving translational studies focused on determining if and how angiotensin II receptor blockade reduces adipose tissue inflammation in obesity. Ultimately these studies may lead to improved clinical recognition of adipose tissue inflammation, in turn, improved therapy and outcomes for these individuals. Public Health Relevance Statement The major objective of the present proposal is to determine if a particular drug used to lower blood pressure also reduces inflammation in fat tissue of obese individuals with high blood pressure. The results of the proposed studies may ultimately lead to improved clinical recognition of the adipose tissue inflammation in obese individuals. Importantly, these findings may lead to specific targets for therapy of adipose tissue inflammation, a factor linked to many obesity-related complications, and, in turn, improved outcomes for obese individuals.