Effects of TNF-a Antagonism in Patients with Obesity and Metabolic Dysregulation

描述(由申请人提供)： 肥胖与脂和糖代谢紊乱密切相关，进而增加心血管发病率和死亡率[1]。据信，这种增加的风险至少部分源于强直性亚临床炎症水平高于正常体重受试者。鉴于多达32%的美国人患有肥胖症[2]，了解肥胖及其伴随的代谢并发症从未像现在这样重要。 我们研究的第一个具体目的是确定使用肿瘤坏死因子-α(TNF-α)拮抗剂依那西普进行长时间、治疗性剂量的抗炎治疗对肥胖和代谢紊乱患者心血管风险标志物的影响。监测的终点将包括人体测量、炎症细胞因子水平、血脂水平、口服葡萄糖耐量测试后的血糖水平、外周动脉测压的血流介导血管扩张以及腹部CT扫描的内脏和皮下脂肪定量。第二个目的是了解这种疗法对这些患者皮下脂肪活检样本中脂肪组织中肿瘤坏死因子-α、可溶性肿瘤坏死因子受体、内皮细胞白细胞黏附标记物、趋化因子、巨噬细胞极化标记物、内质网应激标记物和脂肪细胞因子的影响。40名肥胖和代谢紊乱的患者将被随机接受依那西普或相同的安慰剂治疗6个月。我们的假设是，延长治疗剂量的依那西普治疗将减少这类患者的全身和局部炎症，这样做可能会降低心血管风险并改善胰岛素敏感性。 这项研究将在两个重要方面惠及公众健康。首先，它将有助于澄清 与肥胖相关的心血管并发症的发病机制，肥胖是一种严重的负面健康后果。更好地了解这种情况及其并发症可以反过来导致有效的治疗干预。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。这些信息将对心血管和代谢风险增加的广泛临床和亚临床炎症性疾病具有治疗意义。

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.