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）：该申请提出了两个假设（1），损害AMPK激活的损害使肥胖人类的脂肪组织易于炎症和氧化应激，这反过来又会导致全身性胰岛素抵抗力，（2）在这些药物逆转的情况下，至少通过逐步恢复了这些药物逆转，以恢复这些异常。为了检验这些假设，我们是在研究脂肪组织中发展现有优势的策略，在波士顿大学医学中心（BUMC）的AMPK和密切相关的分子SIRT1，并将其与东部卡罗来纳大学（ECU）进行减肥手术的人类进行临床研究中的优势融为一体。我们的中心假设是从BUMC组的研究中提出的，该研究证明了脂肪组织中的AMPK通过脂解激活，并且通过各种方法（在培养的3T3L1细胞中）抑制其激活。增加氧化应激和单核细胞粘附。反过来，这导致一项针对减肥手术的明显肥胖患者的一项小型研究表明，AMPK活性较低，并且在抗胰岛素耐药性的患者的脂肪组织中炎症标记和趋化因子受体的表达较高（占总胰岛素的70％）。拟议的研究旨在确认和扩展这些发现，并确定观察到的异常是否通过减肥手术逆转。此外，我们将在手术前后对从两个患者组和适当对照的两个患者组中采取的脂肪细胞进行研究，以确定如何通过脂肪解析，氧化和ER应激，基因表达，脂质液滴蛋白和线粒体功能来区分它们。我们还将在初步研究中确定这些参数如何对AMPK和SIRT1激活剂以及肠凝结素的反应。在这些努力中的成功将为随后的多投期药赠款创造科学和临床基础设施，以在减肥手术的情况下研究AMPK和SIRT1，这是两个机构共同努力的公共卫生相关性：代谢综合征，有时被称为肥胖引起的胰岛素抵抗（01R），是一个主要的公共卫生问题，使患者容易患者2型糖尿病，动脉粥样硬化心血管疾病，高血压，甚至某些癌症。了解它在大多数但不是全部肥胖的人中发生的原因以及减肥手术如何逆转可能会对其预防和治疗产生重大影响。