AMPK and adipose tissue biology in bariatric surgery patients

描述(由申请人提供)：本申请涉及两个假设：(1)AMPK活性受损使肥胖者的脂肪组织容易受到炎症和氧化应激的影响，这反过来可能导致系统性胰岛素抵抗；(2)减肥手术至少部分通过恢复AMPK活性来逆转这些和其他异常。为了验证这些假设，我们的战略是发展现有的脂肪组织研究优势， AMPK和一个密切相关的分子SIRT1在波士顿大学医学中心(BUMC)，并将它们与在东卡罗来纳大学(ECU)接受减肥手术的人类临床研究中的优势相结合。我们的中心假设源于BUMC小组的研究，该研究表明脂肪组织中的AMPK是通过脂解激活的，通过各种方式抑制其激活(在培养的3T3L1细胞中)导致 以增加氧化应激和单核细胞的粘附性。这进而导致了一项针对接受减肥手术的明显肥胖患者的小型研究，该研究显示，胰岛素抵抗患者(占总数的70%)脂肪组织中AMPK活性较低，而炎症标记物和趋化因子受体的表达较高。拟议的调查旨在确认和扩大这些发现，并确定所观察到的异常是否可以通过减肥手术逆转。此外，我们将开始对手术前后两组患者的脂肪细胞和适当的对照组进行研究，以确定它们在脂解、氧化和内质网应激、基因表达、脂滴蛋白和线粒体功能等特征上的区别。我们还将在初步研究中确定脂肪细胞中这些参数如何对AMPK和SIRT1激活剂以及胰岛素做出反应。这些努力的成功将为随后的多研究员资助创建科学和临床基础设施，以研究AMPK和SIRT1在两个机构的联合努力下的减肥手术背景 与公共健康相关：代谢综合征，有时被称为肥胖诱导的胰岛素抵抗(01R)，是一个主要的公共健康问题，容易使患者患上2型糖尿病、动脉粥样硬化性心血管疾病、高血压，甚至某些癌症。了解为什么它会发生在大多数但不是所有的肥胖者身上，以及减肥手术是如何逆转它的，这可能对它的预防和治疗具有重要意义。

DESCRIPTION (provided by applicant): This application addresses two hypotheses (1) that impaired AMPK activation predisposes adipose tissue of obese humans to inflammation and oxidative stress, which in turn can result in systemic insulin resistance and (2) that bariatric surgery reverses these and other abnormalities, at least in part by restoring AMPK activity. To test these hypotheses, it is our strategy to develop existing strengths in studying adipose tissue, AMPK and a closely related molecule SIRT1 at Boston University Medical Center (BUMC) and to integrate them with strengths in the clinical investigation of humans undergoing bariatric surgery at Eastern Carolina University (ECU). Our central hypothesis emanated from investigations by the BUMC group which demonstrated that AMPK in adipose tissue is activated by lipolysis and that inhibition of its activation by various means (in cultured 3T3L1 cells) leads to increases in oxidative stress and adhesion of mononuclear cells. This in turn led to a small study in markedly obese patients undergoing bariatric surgery that revealed AMPK activity is lower and the expression of inflammatory markers and chemokine receptors higher in adipose tissue of patients who were insulin resistant (70 percent of total). The proposed investigations are intended to confirm and extend these findings and to determine whether the observed abnormalities are reversed by bariatric surgery. In addition we will initiate studies with adipocytes taken from the two patient groups before and after surgery and appropriate controls, to determine how they are distinguished by such characteristics as lipolysis, oxidative and ER stress, gene expression, lipid droplet proteins and mitochondrial function. We will also determine in preliminary studies how in the adipocytes these parameters respond to AMPK and SIRT1 activators, and to incretins. Success in these endeavors will create the scientific and clinical infrastructure for a subsequent multi-investigator grant to study AMPK and SIRT1 in the setting of bariatric surgery in a joint effort by the two institutions PUBLIC HEALTH RELEVANCE: The metabolic syndrome, sometimes referred to as obesity-induced insulin resistance (01R), is a major public health problem that predisposes patients to type 2 diabetes, atherosclerotic cardiovascular disease, hypertension and even certain cancers. An understanding of why it occurs in most, but not all, obese people and how it is reversed by bariatric surgery could have significant implications for its prevention and treatment.