The AMPK/SIRT1 Partnershipand Its Biological Relevance

AMPK/SIRT1 伙伴关系及其生物学相关性

基本信息

批准号：
8728802
负责人：
NEIL B RUDERMAN
金额：
$ 34.3万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
1979
资助国家：
美国
起止时间：
1979-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8728802
关键词：
5&apos -AMP-activated protein kinase Adipocytes Adipose tissue Affect Apoptosis Biological Caloric Restriction Cell Line Cell physiology Cells Cultured Cells Data Depressed mood Diabetes Mellitus Diabetes prevention Diet Disease Down-Regulation Exercise Fatty Acids Fatty acid glycerol esters Functional disorder Genetic Glucose Grant Histones Hormonal Human Hyperglycemia In Vitro Individual Inflammation Insulin Insulin Resistance Interest Group Islets of Langerhans Joints Lead Link Lipase Lipolysis Liver Longevity Mediator of activation protein Messenger RNA Metabolic Metabolic syndrome Mitochondria Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Obesity Operative Surgical Procedures Oxidative Stress Palmitates Pancreas Patients Peripheral Physiological Play Preparation Proteins Rattus Regulation Rodent Role STK11 gene Signal Transduction Small Interfering RNA Starvation Stress System TNF gene Tissues Visceral Work bariatric surgery clinically relevant diabetes mellitus therapy in vivo inflammatory marker inhibitor/antagonist insulin secretion islet knock-down lipid metabolism loss of function new therapeutic target operation overexpression response subcutaneous tool upstream kinase

5&apos -AMP-activated protein kinase Adipocytes Adipose tissue Affect Apoptosis Biological Caloric Restriction Cell Line Cell physiology Cells Cultured Cells Data Depressed mood Diabetes Mellitus Diabetes prevention Diet Disease Down-Regulation Exercise Fatty Acids Fatty acid glycerol esters Functional disorder Genetic Glucose Grant Histones Hormonal Human Hyperglycemia In Vitro Individual Inflammation Insulin Insulin Resistance Interest Group Islets of Langerhans Joints Lead Link Lipase Lipolysis Liver Longevity Mediator of activation protein Messenger RNA Metabolic Metabolic syndrome Mitochondria Modeling Mus Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Obesity Operative Surgical Procedures Oxidative Stress Palmitates Pancreas Patients Peripheral Physiological Play Preparation Proteins Rattus Regulation Rodent Role STK11 gene Signal Transduction Small Interfering RNA Starvation Stress System TNF gene Tissues Visceral Work bariatric surgery clinically relevant diabetes mellitus therapy in vivo inflammatory marker inhibitor/antagonist insulin secretion islet knock-down lipid metabolism loss of function new therapeutic target operation overexpression response subcutaneous tool upstream kinase

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项目摘要

DESCRIPTION (provided by applicant): It has been proposed that dysregulation of the fuel sensing enzyme AMPK is a pathogenic factor for type 2 diabetes and other disorders linked to the metabolic syndrome and a target for their therapy. Other studies have suggested a similar role for the sirtuin SIRT1, an NAD-dependent histone/protein deacetylases, best known as a possible mediator of the increased longevity caused by caloric restriction. In the preceding grant period, we discovered that SIRT1 can activate AMPK by deacetylating its upstream kinase LKB1 and two other groups found that AMPK can activate SIRT1, suggesting the existence of a SIRT1/AMPK cycle. The applicability of these findings to models other than a few cell lines and their physiological and clinical relevance remain to be established. Upon this background, studies will be carried out in cultured cells, rodents and humans with the following four specific aims: (1) To examine the workings of the AMPK/SIRT1 signaling mechanism in cultured adipocytes and pancreatic ¿-cells (which produce insulin). (2) To determine whether AMPK/SIRT1 signaling interacts with a recently defined glycerolipid/free fatty acid cycle to maintain the integrity and function of adipocytes and ¿-cells. (3) To assess how the two cycles interact with each other in vivo during exercise, starvation/refeeding and diet- induced obesity. (4) To determine if the AMPK/SIRT1 mechanism is depressed in adipose tissue of massively obese humans with insulin resistance. This is a particularly interesting group since we have already found that AMPK activity is diminished in these individuals, compared to comparably obese individuals who are insulin sensitive, and that this is associated with a large increase in the expression of inflammatory markers.

描述（由适用提供）：已经提出，燃料感应酶AMPK的失调是2型糖尿病和其他与代谢综合征相关的疾病的致病因素，也是其治疗的靶标。其他研究表明，SIRTUIN SIRT1（一种NAD依赖性组蛋白/蛋白脱乙酰基酶）的作用相似，最著名的是由热量限制引起的寿命增加的可能介体。在上一个赠款期间，我们发现SIRT1可以通过将其上游激酶LKB1脱乙酰基激活AMPK，而另外两个组发现AMPK可以激活SIRT1，这表明存在SIRT1/AMPK循环。这些发现对除几个细胞系以外的模型的适用性及其物理和临床相关性仍有待确定。在这种背景下，将在培养的细胞，啮齿动物和人类中进行以下四个特定目的进行研究：（1）检查AMPK/SIRT1信号传导机制在培养的脂肪细胞和胰腺中的工作（产生胰岛素）。（2）确定AMPK/SIRT1信号是否与最近定义的甘油/游离脂肪酸循环相互作用，以维持脂肪细胞和细胞的完整性和功能。（3）在运动过程中评估两个周期如何在体内相互作用，饥饿/喂养和饮食引起的肥胖。（4）确定AMPK/SIRT1机制是否在具有胰岛素抵抗的大量肥胖人的脂肪组织中抑制。这是一个特别有趣的群体，因为我们已经发现，与胰岛素敏感的肥胖个体相比，这些个体中的AMPK活性会降低，并且这与炎症标记物表达的大幅增加有关。