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

• 批准号: 8538374
• 负责人: Naji N Abumrad
• 金额: $ 57.07万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538374
• 关键词: Adipose tissue; Affect; Age; Antioxidants; Bariatrics; Biopsy; Body Composition; Body Weight Changes; Body Weight decreased; CD36 gene; Caloric Restriction; Cardiovascular Diseases; Cholecystokinin; Chronic; Comorbidity; Data; Diet; Dinoprost; Drops; Energy Intake; Enzymes; Ethnic Origin; Euglycemic Clamping; Flow Cytometry; Gastric Bypass; Gene Expression; Glucose Clamp; Hepatic; Hormones; Hyperglycemia; Immunohistochemistry; In Vitro; Inflammation; Inflammatory; Infusion procedures; Insulin Resistance; Interleukin-1; Interleukin-10; Interleukin-6; Interruption; Lead; Leptin; Link; Lipolysis; Liver; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measurement; Measures; Metabolic; Metabolism; Methodology; Microdialysis; Mitochondria; Morbid Obesity; NADPH Oxidase; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Overweight; Oxidative Stress; Peptides; Phosphatidylinositols; Phosphotransferases; Plasma; Population; Prevalence; Procedures; Production; Property; Public Health; Reactive Oxygen Species; Risk Factors; Role; Sampling; Sampling Studies; Signal Transduction; Skeletal Muscle; Staging; Stomach; Study Subject; Superoxide Dismutase; TNF gene; Tennessee; Testing; Tissue Microarray; Tissue Sample; Tissues; Triglycerides; Visceral; Weight; bariatric surgery; base; cardiovascular disorder risk; cohort; cytokine; ghrelin; glucose production; glucose uptake; glutathione peroxidase; improved; in vivo; inflammatory marker; insulin sensitivity; insulin signaling; islet amyloid polypeptide; macrophage; monocyte; restoration; sex; stable isotope; subcutaneous; tissue culture

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；美国近60％的人口被认为是肥胖或超重。更令人震惊的是，像PI所在的田纳西州一样，“超级肥胖”（III级肥胖）的患病率增加（III级肥胖）。这种情况与严重的共同病毒有关，例如心血管疾病和2型糖尿病，其中许多归因于慢性炎症，氧化应激和胰岛素抵抗。 Roux-en-Y胃旁路（RYGB）手术是最有效，最可持续的减肥程序。我们和其他人的数据表明，RYGB的许多代谢益处在术后的第一周发生，然后在重大减肥之前。在这些改进之前，胃衍生的生长素蛋白和瘦素的循环水平显着降低，最早发生在RYGB手术过程中胃中中断后15分钟。这些变化与脂肪组织中氧化应激的显着减少相关。一般假设是，RYGB导致胃掺杂组织轴中断，从而导致氧化应激和胰岛素敏感性的立即改善（在第一周内）改善。在特定目标1中，我们将检查RYGB 7天后7天的细胞，组织特异性和全身代谢改变。在热量限制之前和7天之前，将研究两次匹配的对照组（以匹配后乳房饮食），而无需胃中中断：一个带有lagb（腹腔镜调节的胃束带），另一个没有任何手术程序。在特定的目标2中，我们将检查在RYGB后的第一周，在RYGB逆转脂肪组织和胰岛素敏感性中氧化应激的改善后，在第一周是否替换了生长素释放蛋白（恢复到酰化的生长素蛋白比）。我们将利用三种免费和全面的方法：（i）体内研究来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，细胞因子的产生和脂肪溶解。我们将使用磁共振光谱（MRS）和使用MRI和双能X射线吸收仪（DXA）将代谢改善与肝内甘油三酸酯含量相关联和内脏脂肪组织质量。 （ii）离体研究将评估脂肪组织外植体氧化应激和炎症标志物上胃衍生肽的机理方面。 （iii）体外研究将检查：（a）脂肪组织活检中ROS产生以及促氧化应激酶的细胞因子（b）通过流式细胞仪，RT-QPCR和免疫组织化学的脂肪组织巨噬细胞含量（C） ）与脂肪组织和骨骼肌中胰岛素信号传导有关的细胞因子。得出的信息可能导致较少的侵入性外科手术与药理学操纵的结合，以治疗病态肥胖症的酰基化生长素蛋白和/或瘦素水平。