Effects of TNF-alpha Antagonism in Patients with Obesity and Metabolic Dysregulat

TNF-α拮抗剂对肥胖和代谢失调患者的影响

• 批准号: 7803389
• 负责人: Markella V. Zanni
• 金额: $ 5.77万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7803389
• 关键词: Abdomen; Acute-Phase Reaction; Adhesions; Adipocytes; Adipose tissue; American; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Biopsy; C-reactive protein; Cardiovascular system; Clinical; Development; Disease; Dissociation; Dose; Double-Blind Method; Endothelial Cells; Etanercept; Fatty acid glycerol esters; Functional disorder; Glucose; Health; Hepatic; Human; Immunosuppression; Individual; Inflammation; Inflammatory; Insulin Resistance; Interleukin-6; Intervention; Lead; Leukocyte Adhesion Molecules; Leukocyte-Adhesion Receptors; Leukocytes; Link; Lipids; Measurement; Measures; Mediating; Metabolic; Monitor; Morbidity - disease rate; OGTT; Obese Mice; Obesity; Outcome Measure; Pathogenesis; Patients; Peripheral; Placebos; Population; Positioning Attribute; Process; Production; Public Health; Randomized; Relative (related person); Research; Research Design; Rheumatoid Arthritis; Risk; Risk Marker; Sampling; Stimulus; TNF gene; Therapeutic; Therapeutic Intervention; Time; Tumor Necrosis Factor-alpha; Vasodilation; Visceral; Weight; X-Ray Computed Tomography; adiponectin; arterial tonometry; atherogenesis; cardiovascular risk factor; cell type; chemokine; chemokine receptor; cytokine; diabetic patient; endoplasmic reticulum stress; glucose metabolism; glucose tolerance; human TNF protein; improved; insulin sensitivity; macrophage; mortality; patient population; receptor; resistin; response; stem; subcutaneous; therapy duration

DESCRIPTION (provided by applicant): Obesity is strongly associated with dysregulation of lipid and glucose metabolism, and in turn with increased risk of cardiovascular morbidity and mortality [1]. This increased risk is believed to stem, at least in part, from a level of tonic, subclinical inflammation higher than that seen in normal-weight subjects. Understanding obesity and its attendant metabolic complications has never been more important, given that up to 32% of Americans suffer from this condition [2]. The first specific aim of our study is to determine the effect of prolonged, therapeutic dose anti-inflammatory therapy with a TNF-alpha (TNF-a) antagonist, etanercept, on markers of cardiovascular risk in patients with obesity and metabolic dysregulation. Monitored endpoints will include anthropometric measurements, levels of inflammatory cytokines, lipid levels, glucose levels in response to oral glucose tolerance testing, flow-mediated vasodilation on peripheral arterial tonometry, and visceral and subcutaneous fat quantification on abdominal CT scanning. The second aim is to understand the effect of such therapy on adipose tissue expression of TNF-a, soluble TNF-a receptors (sTNFR's), endothelial cell leukocyte adhesion markers, chemokines, macrophage polarization markers, endoplasmic reticulum (ER) stress markers, and adipocytokines, as measured in biopsied subcutaneous fat samples from these patients. Forty patients with obesity and metabolic dysregulation will be randomized to receive etanercept or identical placebo for six months. Our hypothesis is that prolonged, therapeutic dose etanercept treatment will decrease both systemic and local inflammation in this patient population, and in so doing may attenuate cardiovascular risk and improve insulin sensitivity. This research will benefit the public health in two important ways. First, it will help to elucidate the pathogenesis of cardiovascular complications associated with obesity, a rampant condition with profoundly negative health consequences. A better understanding of this condition and its complications could in turn lead to effective therapeutic interventions. Second, it will help explain the link between obesity, inflammation, endothelial dysfunction, and insulin resistance. Such information will have treatment implications for a broad spectrum of clinical and subclinical inflammatory conditions in which cardiovascular and metabolic risk is increased.

描述（由申请人提供）： 肥胖与脂质和葡萄糖代谢的失调密切相关，而心血管发病率和死亡率的风险增加[1]。人们认为，这种增加的风险至少部分是由于比正常受试者高的强直性，亚临床炎症水平更高。鉴于多达32％的美国人患有这种情况，了解肥胖症及其随之而来的代谢并发症从未如此重要[2]。 我们研究的第一个具体目的是确定用TNF-Alpha（TNF-A）拮抗剂（Etanercept）延长治疗性剂量抗炎治疗对心血管风险标志物对肥胖症和代谢失调患者的心血管风险标志的影响。受监测的终点将包括人体测量值，炎症细胞因子的水平，脂质水平，响应口服葡萄糖耐受性测试的葡萄糖水平，外周科动脉神经术对血糖介导的血管舒张，以及对腹部CT扫描的内心和皮下脂肪定量。第二个目的是了解这种疗法对TNF-A，可溶性TNF-A受体（STNFR）的脂肪组织表达的影响，内皮细胞白细胞粘附标记物，趋化因子，巨噬细胞极化标记物，内质网应激标志物（ER）压力标志物（ER）的生物，以及这些患者的量表，并分散了这些患者的量度，并分散了这些量。有40例肥胖症和代谢失调的患者将被随机分配以接受依那耐酸或相同的安慰剂六个月。我们的假设是，延长的治疗性剂量疗程治疗将减少该患者人群的全身性和局部炎症，因此，这样做可能会减轻心血管风险并提高胰岛素敏感性。 这项研究将以两种重要方式使公共卫生受益。首先，它将有助于阐明 与肥胖相关的心血管并发症的发病机理，肥胖状况猖ramp，具有严重负面的健康后果。更好地了解这种情况及其并发症可能会导致有效的治疗干预措施。其次，它将有助于解释肥胖，炎症，内皮功能障碍和胰岛素抵抗之间的联系。此类信息将对多种临床和亚临床炎症条件具有治疗意义，其中心血管和代谢风险增加。