AMPK and adipose tissue biology in bariatric surgery patients

描述（由申请人提供）：本申请提出了两个假设（1）AMPK 激活受损使肥胖人群的脂肪组织易发生炎症和氧化应激，进而导致全身胰岛素抵抗；（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。为了检验这些假设，我们的策略是发展研究脂肪组织的现有优势， 波士顿大学医学中心 (BUMC) 的 AMPK 和密切相关的分子 SIRT1，并将它们与东卡罗来纳大学 (ECU) 接受减肥手术的人类临床研究的优势相结合。 我们的中心假设源自 BUMC 小组的研究，该研究表明脂肪组织中的 AMPK 通过脂解作用被激活，并且通过各种方式（在培养的 3T3L1 细胞中）抑制其激活会导致 增加氧化应激和单核细胞粘附。这反过来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，结果显示，胰岛素抵抗患者（占总数的 70%）的脂肪组织中 AMPK 活性较低，而炎症标记物和趋化因子受体的表达较高。拟议的研究旨在证实和扩展这些发现，并确定观察到的异常是否可以通过减肥手术逆转。此外，我们将对手术前后两个患者组的脂肪细胞和适当的对照进行研究，以确定如何通过脂肪分解、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来区分它们。我们还将在初步研究中确定脂肪细胞中这些参数如何响应 AMPK 和 SIRT1 激活剂以及肠促胰岛素。这些努力的成功将为随后的多研究者资助创建科学和临床基础设施，以在两个机构的共同努力下在减肥手术中研究 AMPK 和 SIRT1 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 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。了解为什么大多数（但不是全部）肥胖者会出现这种情况，以及如何通过减肥手术逆转这种情况，可能对其预防和治疗产生重大影响。

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.