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）：