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AMPK and adipose tissue biology in bariatric surgery patients

减肥手术患者的 AMPK 和脂肪组织生物学

基本信息

批准号：
8268586
负责人：
NEIL B RUDERMAN
金额：
$ 49.21万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-16 至 2014-06-30
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：本申请提出了两个假设：（1）AMPK活化受损使肥胖人的脂肪组织易于发生炎症和氧化应激，进而导致全身性胰岛素抵抗;（2）减肥手术至少部分通过恢复AMPK活性逆转这些和其他异常。为了验证这些假设，我们的策略是发展现有的研究脂肪组织的优势， AMPK和一种密切相关的分子SIRT 1在波士顿大学医学中心（BUMC），并整合他们的优势，在临床研究的人接受减肥手术在东卡罗莱纳大学（ECU）。我们的中心假设来自于BUMC小组的研究，该研究表明脂肪组织中的AMPK通过脂解被激活，并且通过各种手段（在培养的3 T3 L1细胞中）抑制其激活导致增加氧化应激和单核细胞粘附。这反过来又导致了一项对接受减肥手术的显着肥胖患者的小型研究，该研究显示AMPK活性较低，胰岛素抵抗患者脂肪组织中炎症标志物和趋化因子受体的表达较高（占总数的70%）。拟定的研究旨在确认和扩展这些发现，并确定所观察到的异常是否可通过减肥手术逆转。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进行研究，以确定它们如何通过脂解，氧化和ER应激，基因表达，脂滴蛋白和线粒体功能等特征进行区分。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SIRT 1激活剂以及肠促胰岛素做出反应。这些努力的成功将为随后的多研究者资助创造科学和临床基础设施，以研究AMPK和SIRT 1在减肥手术中的作用，这两个机构将共同努力公共卫生关系：代谢综合征，有时被称为肥胖诱导的胰岛素抵抗（01 R），是一个主要的公共卫生问题，使患者易患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）肥胖者身上，以及减肥手术如何逆转它，可能会对其预防和治疗产生重大影响。