Inflammation in obesity: Modulation by Weight Loss

肥胖中的炎症：通过减肥进行调节

• 批准号: 6960370
• 负责人: Paresh Dandona
• 金额: $ 28.28万
• 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/6960370
• 关键词: NAD(P)H dehydrogenase; adipose tissue; atherosclerosis; clinical research; diabetes risk; enzyme inhibitors; free radical oxygen; gene expression; human subject; inflammation; insulin sensitivity /resistance; monocyte; nuclear factor kappa beta; obesity; oxidative stress; tumor necrosis factor alpha; weight loss

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)：在过去的二十年里，肥胖症在美国和世界范围内的流行程度显著增加。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。有研究表明，肥胖是一种促氧化和促炎状态，可能与长期大量营养素摄入增加有关。单个核细胞(MNC)参与动脉壁的致动脉粥样硬化，也参与脂肪组织的炎症反应。这项研究将检验肥胖者的外周血单核细胞与正常瘦人相比处于促炎状态的假设。我们的第一个目标是通过在单核细胞中显示肥胖与促炎转录因子NFkappaB激活之间的联系，从而建立肥胖与炎症早期步骤之间的联系，这导致促炎基因(TNFpha、IL-6、MIF和MMP-9)的表达增加。此外，还将研究肥胖受试者和消瘦受试者在氧化应激方面的差异，如ROS生成、NADPH氧化酶、氧化脂质、氧化蛋白质和异前列腺素。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单核细胞和脂肪组织中的表达之间的相关性。我们的第四个目标是研究肥胖者中已知的肱动脉异常的缺血性血管扩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性介质，如肿瘤坏死因子α，减少了血管扩张剂内皮一氧化氮(NO)的可获得性。不对称二甲基精氨酸(ADMA)是一种内源性一氧化氮合酶抑制剂，已知在肥胖时会增加，将在减肥前后进行测量。此外，炎症和氧化应激介质的减少将与减肥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来证实1)肥胖是一种在单核细胞和脂肪组织中观察到的促炎症和促氧化应激状态；2)通过减肥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的改善；3)从长远来看，氧化应激和炎症的减少可能有助于预防动脉粥样硬化。