Role of the Omentum in the Treatment of Morbid Obesity

大网膜在病态肥胖治疗中的作用

• 批准号: 6909198
• 负责人: Naji N Abumrad
• 金额: $ 67.44万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6909198
• 关键词: African American; adipocytes; adipose tissue; bioenergetics; caucasian American; clinical research; cytokine; diabetes risk; fatty acid metabolism; gastrointestinal surgery; gene expression; glucose clamp technique; glucose metabolism; human morbidity; human subject; inflammation; insulin dependent diabetes mellitus; insulin sensitivity /resistance; macrophage; obesity; peritoneum; quality of life; racial /ethnic difference; stomach /intestine bypass

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.

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。中央肥胖代表了2型糖尿病（T2DM）和心血管并发症的主要风险。脂肪组织，尤其是脑型（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（RYGB）是导致体重减轻的唯一方式。我们的研究和其他研究表明，RYGB有效地在很大一部分患者中逆转T2DM。这些机制仍然未知。我们有证据表明，手术后的体重减轻不是代谢改善背后的唯一机制。改进很早（在10天之内），并在任何重大的体重减轻之前；它们与内脏的脂肪分布有关，并且存在种族偏见，与高加索人相比，非洲裔美国人表现出钝性和延迟的反应。该应用的中心假设是，减肥手术后的胰岛素敏感性的改善是种族偏见的，并在术后（10-30天）开始（10-30天）开始，并由能量相关肽分泌的变化介导，而长期作用（大于1个月）是由炎症因子下降介导的。此外，我们假设去除小膜与减肥手术相结合可以增强胰岛素抵抗的逆转，并会减少对减肥手术的响应种族差异。我们提出了一项在高加索和非裔美国人病态肥胖患者中进行的随机研究，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，第二名患者进行了超牙切除术。提出了三个具体目标。在特定目标1中，我们将确定RYGB后代谢改善的机制。具体而言，我们将检查与能量相关肽和炎症反应的分泌和作用的改变。具体目标2探讨了非裔美国人患者RYGB后钝化/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。我们将探讨居民巨噬细胞在介导相关炎症反应中的作用。具体目标3将确定将渗透切除术与RYGB加速并持续改善，尤其是在非裔美国人的人群中。研究包括确定区域脂肪储存，脂肪细胞大小，组织巨噬细胞含量以及巨噬细胞基因表达，昼夜和食物诱导的脂肪因子分泌（瘦素，抵抗蛋白和脂联素）以及能量调节肽（如ghrelin and Pyy）。参数将与炎症标记（例如CRP，IL-6，TNF-A2R等）的时间依赖性变化以及使用高胰岛素纤维血糖夹的组织胰岛素反应能力相关。