Inflammation in obesity: Modulation by Weight Loss

肥胖中的炎症：通过减肥进行调节

• 批准号: 7231003
• 负责人: Paresh Dandona
• 金额: $ 30.58万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7231003
• 关键词: Adipocytes; Adipose tissue; Adult; Arginine; Atherosclerosis; Binding; Biopsy; Blood Vessels; Blood specimen; Body Weight decreased; Caloric Restriction; Cells; Cholesterol; Chronic; Diet; Dilatation - action; Education; Euglycemic Clamping; F2-Isoprostanes; Fatty acid glycerol esters; Gelatinase B; Gene Expression; Generations; Genes; Genetic Transcription; Glucose Clamp; Goals; Inflammation; Inflammatory; Intake; Interleukin-6; Isoprostanes; Lead; Leukocytes; Link; Macronutrients Nutrition; Measures; Mediating; Mediator of activation protein; Messenger RNA; Migration Inhibitory Factor; Mononuclear; NADPH Oxidase; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Extract; Obesity; Oxidative Stress; Pathological Dilatation; Peripheral; Peripheral Blood Mononuclear Cell; Plasma; Prevalence; Prevention; Protein Isoforms; Proteins; Randomized; Reactive Oxygen Species; Recommendation; Research; Research Personnel; Risk Factors; Study models; Testing; Tissues; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Tyrosine; United States; Upper arm; Vasodilation; Vasodilation disorder; Vasodilator Agents; Week; brachial artery; human TNF protein; human subject; inhibitor/antagonist; insulin sensitivity; mRNA Expression; oxidized lipid; p65; phenylpyruvate tautomerase; programs; protein expression; subcutaneous; transcription factor

DESCRIPTION (provided by applicant): The prevalence of obesity has increased markedly over the last two decades in the United States and worldwide. Obesity is a major risk factor for diabetes type 2 and atherosclerosis, both of which are associated with inflammation. It has been suggested that obesity is a pro-oxidative and pro-inflammatory state which may be related to chronically increased macronutrient intake. Mononuclear cells (MNC) participate in atherogenicity in the arterial wall and also mediate inflammation in adipose tissue. This study will test the hypothesis that peripheral blood MNC in the obese are in a pro-inflammatory state when compared with those of normal lean subjects. Our first goal is to establish a link between obesity and the early steps of inflammation by showing an association between obesity and the pro-inflammatory transcription factor NFkappaB activation in MNC, which results in an increase in pro-inflammatory gene expressions (TNFalpha, IL-6, MIF and MMP-9). In addition, the differences in oxidative stress as reflected in reactive oxygen species (ROS) generation, NADPH oxidase, oxidized lipids, oxidized proteins and isoprostane between obese and lean subjects will be studied. Our second goal is to test the effect of weight loss on these inflammatory mediators and oxidative stress. Our third goal is to establish a correlation in the expression of these inflammatory mediators in MNC and adipose tissue from fat biopsies. Our fourth goal is to investigate whether the abnormal ischemic vasodilatation of the brachial artery known to occur in the obese will revert to normal following weight loss since abnormal vascular reactivity may be due to oxidative stress and inflammatory mediators like TNFalpha which reduce the availability of endothelial nitric oxide (NO), a vasodilator. Asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthase known to be increased in obesity, will be measured before and after weight loss. In addition, the reduction of the inflammatory and oxidative stress mediators will be correlated with increased insulin sensitivity following weight loss. This study represents a unique opportunity to establish that 1) obesity is a pro-inflammatory and pro-oxidative stress state as observed in MNC and adipose tissue; 2) The reduction in inflammation and oxidative stress by weight loss may lead to improvement in abnormalities in vascular reactivity associated with obesity; 3) The reduction in oxidative stress and inflammation may in the long term potentially contribute to the prevention of atherosclerosis.

描述（由申请人提供）：在过去二十年中，美国和全世界肥胖症的患病率显著增加。肥胖是2型糖尿病和动脉粥样硬化的主要危险因素，这两种疾病都与炎症有关。有人认为，肥胖是一种促氧化和促炎症状态，这可能与长期增加的大量营养素摄入有关。单核细胞（MNC）参与动脉壁的致动脉粥样硬化性，也介导脂肪组织的炎症。本研究将检验这一假设，即与正常瘦型受试者相比，肥胖者外周血MNC处于促炎状态。我们的第一个目标是通过显示肥胖与MNC中促炎转录因子NF κ B激活之间的关联来建立肥胖与炎症早期阶段之间的联系，这导致促炎基因表达（TNF α，IL-6，MIF和MMP-9）增加。此外，将研究肥胖和瘦受试者之间的氧化应激差异，如反应性氧簇（ROS）生成、NADPH氧化酶、氧化脂质、氧化蛋白和异前列烷。我们的第二个目标是测试减肥对这些炎症介质和氧化应激的影响。我们的第三个目标是建立这些炎症介质在MNC和脂肪组织中的相关性。我们的第四个目标是研究已知发生在肥胖者中的肱动脉的异常缺血性血管舒张是否会在体重减轻后恢复正常，因为异常的血管反应性可能是由于氧化应激和炎症介质如TNF α，其减少了血管舒张剂内皮一氧化氮（NO）的可用性。将在体重减轻前后测量不对称二甲基精氨酸（ADMA）（一种已知在肥胖症中增加的一氧化氮合酶内源性抑制剂）。此外，炎症和氧化应激介质的减少将与体重减轻后胰岛素敏感性的增加相关。这项研究提供了一个独特的机会，以确定：1）肥胖是一种促炎和促氧化应激状态，如在MNC和脂肪组织中观察到的; 2）通过体重减轻减少炎症和氧化应激可能导致与肥胖相关的血管反应性异常改善; 3）氧化应激和炎症的减少可能长期潜在地有助于预防动脉粥样硬化。