RYGB Improves Metabolism by Interrupting the Gastric Adipose Tissue Axis

描述(申请人提供)：肥胖是一个主要的公共健康问题；近60%的美国人口被认为是肥胖或超重。更令人担忧的是，在一些地方，“超级肥胖症”(III级肥胖症)的患病率增加，达到人口的7%，就像PI居住的田纳西州一样。这种情况与严重的共病有关，如心血管疾病和2型糖尿病，其中许多可归因于慢性炎症、氧化应激和胰岛素抵抗。Roux-en-Y胃旁路手术(RYGB)是最有效和最可持续的减肥方法。我们和其他人的数据显示，RYGB的许多代谢益处都发生在术后第一周，即显著减肥之前。在这些改善之前，胃源性Ghrelin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分钟就发生了。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-脂肪组织轴中断，导致氧化应激和胰岛素敏感性立即(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。两组匹配的对照组将在限制热量(以匹配RYGB后的饮食)之前和之后7天进行研究，而不中断胃：一组接受腹腔镜调整胃束带(LAGB)，另一组不进行任何外科手术。在具体目标2中，我们将研究RYGB后第一周的Ghrelin替代(未酰化Ghrelin与酰化Ghrelin比率的恢复)是否逆转脂肪组织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，以评估组织特定的氧化应激，细胞因子的产生和脂解。我们将使用磁共振波谱(MRS)将代谢改善与肝脏内甘油三酯含量相关联，并使用MRI和双能X射线吸收法(DXA)将内脏脂肪组织质量与代谢改善相关联。(Ii)体外研究将评估胃源性多肽对脂肪组织外植体中氧化应激和炎症标记物的作用机制。(Iii)体外研究将检测以下方面的变化：(A)脂肪组织活检组织中产生ROS的细胞因子以及氧化应激酶和抗氧化酶；(B)通过流式细胞仪、RT-qPCR和免疫组织化学检测脂肪组织巨噬细胞含量；(C)参与脂肪组织和骨骼肌中胰岛素信号转导的细胞因子。所获得的信息可能导致将侵入性较小的外科手术与治疗病态肥胖症的酰化生长激素和/或瘦素水平的药物操作相结合。

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.