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RYGB Improves Metabolism by Interrupting the Gastric Adipose Tissue Axis

RYGB 通过中断胃脂肪组织轴来改善新陈代谢

基本信息

批准号：
9261057
负责人：
Naji N Abumrad
金额：
$ 25.52万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-21 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9261057
关键词：
RYGB Improves Metabolism Interrupting Gastric

项目摘要

DESCRIPTION (provided by applicant): Obesity is a major public health problem; nearly 60% of the US population is considered obese or overweight. More alarming is the increase in prevalence of "super-obesity" (Class III obese) reaching in some localities 7% of the population, as in Tennessee where the PI resides. This condition is associated with severe co- morbidities, such as cardiovascular disease and type 2 diabetes, many of which are attributed to chronic inflammation, oxidative stress and insulin resistance. Roux-en-Y gastric bypass (RYGB) surgery is the most effective and sustainable weight loss procedure. Data of ours and others have shown that many of the metabolic benefits of RYGB occur in the first week postoperatively, prior to significant weight loss. These improvements are preceded by significant reductions in the circulating levels of gastric-derived ghrelin and leptin, occurring as early as 15 minutes after the surgical interruption of stomach during the RYGB procedure. These changes associate with significant reductions in oxidative stress in adipose tissue. The general hypothesis is that RYGB results in interruption of a gastric-adipose tissue axis leading to immediate (within the first week) improvements in oxidative stress and insulin sensitivity. In specific aim 1 we will examine the cellular, tissue-specific and whole-body metabolic alterations 7 days following RYGB. Two cohorts of matched controls will be studied before and 7 days following caloric restriction (to match the post-RYGB diet) without stomach interruption: one with LAGB (laparoscopic adjusted gastric banding) and the other without any surgical procedure. In specific aim 2 we will examine whether ghrelin replacement (restoration of unacylated to acylated ghrelin ratio) in the first week following RYGB reverses improvements in oxidative stress in adipose tissue and in insulin sensitivity. We will utilize three complimentary and comprehensive approaches: (i) In vivo studies to determine insulin sensitivity in liver and skeletal muscle and microdialysis of subcutaneous adipose tissue to assess tissue-specific oxidative stress, cytokine production and lipolysis. We will correlate metabolic improvements to intra-hepatic triglyceride content using magnetic resonance spectroscopy (MRS), and visceral adipose tissue mass using MRI and dual-energy x-ray absorptiometry (DXA). (ii) Ex vivo studies will assess mechanistic aspects of stomach-derived peptides on markers of oxidative stress and inflammation in adipose tissue explants. (iii) In vitro studies will examine changes in: (a) cellular factors of ROS production and pro- and anti-oxidative stress enzymes in adipose tissue biopsies (b) adipose tissue macrophage content via flow cytometry, RT-qPCR and immunohistochemistry (c) cellular factors involved in insulin signaling in adipose tissue and skeletal muscle. The information derived could lead to the combination of less invasive surgical procedures with pharmacologic manipulation of the levels of acylated ghrelin and/or leptin for the treatment of morbid obesity.

描述（由申请人提供）：肥胖是一个主要的公共卫生问题;近60%的美国人口被认为是肥胖或超重。更令人担忧的是“超级肥胖”（III级肥胖）患病率的增加，在一些地区达到人口的7%，如在PI居住的田纳西州。这种情况与严重的共病有关，如心血管疾病和2型糖尿病，其中许多是由于慢性炎症，氧化应激和胰岛素抵抗。Roux-en-Y胃旁路手术（RYGB）是最有效和可持续的减肥手术。我们和其他人的数据表明，RYGB的许多代谢益处发生在术后第一周，在体重显著减轻之前。在这些改善之前，胃源性生长激素释放肽和瘦素的循环水平显著降低，早在RYGB手术期间胃手术中断后15分钟发生。这些变化与脂肪组织中氧化应激的显著减少有关。一般的假设是RYGB导致胃脂肪组织轴的中断，导致氧化应激和胰岛素敏感性的立即（在第一周内）改善。在具体目标1中，我们将检查RYGB后7天的细胞、组织特异性和全身代谢变化。将在热量限制（以匹配RYGB后饮食）之前和之后7天研究匹配对照的两个队列，而不中断胃：一个使用LAGB（腹腔镜调整的胃束带术），另一个没有任何外科手术。在具体目标2中，我们将检查在RYGB后的第一周内的生长素释放肽替代（未酰化与酰化生长素释放肽比率的恢复）是否逆转脂肪组织中的氧化应激和胰岛素敏感性的改善。我们将利用三种互补和全面的方法：（i）体内研究，以确定肝脏和骨骼肌中的胰岛素敏感性，以及皮下脂肪组织的微透析，以评估组织特异性氧化应激，细胞因子产生和脂解。我们将使用磁共振波谱（MRS）将代谢改善与肝内甘油三酯含量相关联，使用MRI和双能X射线吸收测定法（DXA）将内脏脂肪组织质量相关联。(ii)离体研究将评估胃源性肽对脂肪组织外植体中氧化应激和炎症标志物的机制方面。(iii)体外研究将检查以下方面的变化：（a）脂肪组织活检中ROS产生的细胞因子以及促氧化应激酶和抗氧化应激酶（B）通过流式细胞术、RT-qPCR和免疫组织化学检测的脂肪组织巨噬细胞含量（c）脂肪组织和骨骼肌中胰岛素信号传导相关的细胞因子。所得到的信息可能导致结合微创外科手术与药理学操纵的水平酰化生长激素释放肽和/或瘦素治疗病态肥胖症。