Role of the Omentum in the Treatment of Morbid Obesity

描述（由申请人提供）：肥胖通常与胰岛素抵抗和炎症细胞因子的异常产生有关。中心性肥胖是2型糖尿病（T2DM）和心血管并发症的主要危险因素。脂肪组织，特别是网膜（脂肪细胞和常驻巨噬细胞）释放几种细胞因子。减肥手术，特别是Roux-en-Y胃旁路手术（RYGB）是唯一能持续减肥的方式。我们的研究和其他研究表明，RYGB对高比例的T2DM患者有效。其机制尚不清楚。我们有证据表明，手术后体重减轻并不是代谢改善背后的唯一机制。这种改善发生在术后很早就（10天内），在任何显著的体重减轻之前；它们与内脏脂肪分布有关，并且存在种族偏见，非洲裔美国人的反应比白种人迟钝和延迟。本应用的中心假设是，减肥手术后胰岛素敏感性的改善存在种族偏见，并在术后早期（10-30天）开始，由能量相关肽分泌的变化介导，而长期效应（大于1个月）由炎症因子的下调介导。此外，我们假设切除大网膜与减肥手术相结合可以增强胰岛素抵抗的逆转，并将减少对减肥手术的反应的种族差异。我们建议在高加索和非裔美国人病态肥胖患者中进行随机研究，以评估葡萄糖和脂肪酸代谢的变化。患者将被随机分为两组，一组单独使用RYGB，另一组使用RYGB联合网膜切除术。提出了三个具体目标。在Specific Aim 1中，我们将确定RYGB后代谢改善的机制。具体来说，我们将研究能量相关肽的分泌和作用以及炎症反应的变化。特异性目标2探讨了非裔美国患者RYGB后迟钝/延迟代谢改善的机制。我们将使用肌肉、内脏和周围脂肪组织的微阵列分析来检查两个种族差异的遗传基础。我们将探讨巨噬细胞在介导相关炎症反应中的作用。具体目标3将确定是否联合网膜切除术与RYGB加速和维持改善，特别是在非洲裔美国人人口。这些研究包括区域脂肪储存、脂肪细胞大小、组织巨噬细胞含量和巨噬细胞基因表达的测定、昼夜和食物诱导的脂肪因子（瘦素、抵抗素和脂联素）和能量调节肽（如胃饥饿素和PYY）的分泌。参数将与炎症标志物（如CRP、IL-6、TNF-a2R等）的时间依赖性变化以及使用高胰岛素正糖钳的组织胰岛素反应性相关。

DESCRIPTION (provided by the applicant): Obesity is often associated with insulin resistance and abnormal production of inflammatory cytokines. Central obesity represents a major risk for the development of type 2 diabetes mellitus (T2DM) and cardiovascular complications. Adipose tissue and especially omentum (adipocytes and resident macrophages) release several cytokines. Bariatric surgery and specifically Roux-en-Y gastric bypass (RYGB) is the only modality that results in sustained weight loss. Our studies and those of others demonstrate that RYGB is effective in reversing T2DM in a high proportion of patients. The mechanisms remain unknown. We have evidence showing that weight loss after surgery is not the sole mechanism behind the metabolic improvements. The improvements occur very early (within 10 days) post-op and precede any significant weight loss; they are related to visceral fat distribution and are racially biased, with African Americans showing blunted and more delayed responses than Caucasians. The central hypotheses of this application is that improvements in insulin sensitivity after bariatric surgery are racially biased and begin early in the postoperative period (10-30 days) and are mediated by changes in the secretion of energy-related peptides, while the long-term effects (greater than 1 month) are mediated by down-regulation of inflammatory factors. Additionally, we hypothesize that the removal of the omentum in combination with bariatric surgery enhances the reversal of the insulin resistance and will diminish the racial differences in response to bariatric surgery. We propose a randomized study in Caucasian and African American morbidly obese patients to evaluate changes in glucose and fatty acid metabolism. Patients will be randomized to two groups, one with RYGB alone and the second with RYGB with omentectomy. Three specific aims are proposed. In Specific Aim 1, we will determine the mechanism for the metabolic improvements after RYGB. Specifically, we will examine alterations in the secretion and action of energy related peptides and inflammatory responses. Specific Aim 2 explores the mechanism for the blunted/delayed metabolic improvement after RYGB in African American patients. We will examine the genetic basis for differences in the two races using microarray analysis of muscle and visceral and peripheral adipose tissues. We will explore the role of resident macrophages in mediating associated inflammatory responses. Specific Aim 3 will determine if combining omentectomy with RYGB accelerates and sustains improvements especially in the African American population. The studies include determination of regional fat stores, adipocyte size, tissue macrophage content and macrophage gene expression, diurnal and food-induced secretion of adipokines (leptin, resistin and adiponectin) and of energy regulating-peptides such as ghrelin and PYY. Parameters will be correlated with time dependent changes in inflammatory markers (e.g. CRP, IL-6, TNF-a2R, etc.) and with tissue insulin responsiveness using hyperinsulinemic euglycemic clamps.