Angiotensin II Receptor Blockade and Adipose Tissue Inflammation in Obesity

点击翻译按钮获取中文摘要

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.