AdPLA function in adipose lipid metabolism

AdPLA 在脂肪脂质代谢中的功能

• 批准号: 8127738
• 负责人: Marcia J Abbott
• 金额: $ 4.31万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-01-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127738
• 关键词: 3T3-L1 Cells; Address; Adenylate Cyclase; Adipocytes; Adipose tissue; Arachidonic Acids; Binding; Coupled; Cyclic AMP; Development; Dinoprostone; Disease; Disease Progression; Epidemic; Esters; Fasting; Fatty Acids; Fatty acid glycerol esters; Goals; Heart Diseases; Hydrolysis; In Vitro; Incidence; Insulin; Knock-out; Knockout Mice; Laboratories; Link; Lipolysis; Liver; Longevity; Mediating; Mentors; Metabolism; National Research Service Awards; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Pathology; Pathway interactions; Phospholipase A2; Phospholipids; Prevalence; Prevention therapy; Process; Production; Prostaglandins; Regulation; Reporting; Research; Role; Signal Transduction; Skeletal Muscle; Societies; Subfamily lentivirinae; Time; Tissues; Triglycerides; fatty acid metabolism; feeding; in vivo; lipid metabolism; overexpression; prevent; prostaglandin EP3 receptor; research study; small hairpin RNA

DESCRIPTION (provided by applicant): Obesity is a growing and serious epidemic in our modern society leading to the development of multiple detrimental pathologies. Sustained obesity has been linked to numerous diseases and disorders including type 2 diabetes. In turn, type 2 diabetes is known to be caused in part by alterations in fatty acid (FA) metabolism. Adipose tissue is responsible for the lipoylsis of stored triacylglycerols (TAG), which provides the necessary FA to other organs for energy use. Regulating fuel supply in the form of FA, during times of energy shortage, is a unique function of adipose tissue. Elucidating the mechanism by which triacylglycerol hydrolysis occurs is essential. Thus, understanding lipolytic processes is important in preventing dysregulation of TAG metabolism and obesity. An adipocyte specific phospholipase A2, AdPLA, has been recently identified. AdPLA has been reported to be involved in the local regulation of lipolysis. AdPLA expression was determined to be decreased with fasting and increased with insulin. It was found that during feeding/insulin treatment, AdPLA facilitates the production of adipocyte-derived prostaglandin 2 (PGE2). It has been proposed that secreted PGE2, by binding to the G1i-coupled EP3 receptor, suppresses lipolysis through inhibition of adenylate cyclase and lower cAMP levels. The goal of the proposed research in this NRSA proposal is to clearly establish the role of AdPLA-PGE2-EP3 signaling in the regulation of lipolysis in adipose tissue. Aim 1 will determine if AdPLA inhibits lipolysis via PGE2 production in adipose specific conditional knockout mice. Adipose tissue specific AdPLA knockout mice will be used to address aim 1. Aim 2 will examine if EP3 is required in the regulation of lipolysis by AdPLA in adipose tissue in vivo. EP3 conditional knockout mice will be used to examine aim 2. Aim 3 will further elucidate the mechanism of the AdPLA-PGE2-EP3 pathway in the regulation of lipolysis in vitro by employing primary adipocytes from the AdPLA and EP3 conditional knockout mice as well as 3T3-L1 studies. It is essential to firmly understand this regulation as it may provide beneficial therapies for the prevention and/or treatment of disease progression such as type 2 diabetes. PUBLIC HEALTH RELEVANCE: The incidence of obesity in our society is apparent and has grown exponentially over the past decade. Obesity has been associated with a decreased lifespan as well as with the development of multiple diseases and disorders such as type 2 diabetes and heart disease. The goal of this study is to understand how the fat tissue breaks down triglycerides which assists other organs to use fat as a fuel. By understanding this process possible treatments for increasing fat use may be discovered and possibly reduce the prevalence of obesity.

描述（由申请人提供）：肥胖是现代社会中一种日益严重的流行病，导致多种有害病症的发展。持续肥胖与包括 2 型糖尿病在内的多种疾病和病症有关。反过来，已知 2 型糖尿病部分是由脂肪酸 (FA) 代谢的改变引起的。脂肪组织负责储存的三酰甘油 (TAG) 的脂解，为其他器官提供能量使用所需的 FA。在能量短缺期间以 FA 的形式调节燃料供应是脂肪组织的独特功能。阐明三酰甘油水解发生的机制至关重要。因此，了解脂肪分解过程对于预防 TAG 代谢失调和肥胖非常重要。最近鉴定出一种脂肪细胞特异性磷脂酶 A2，即 AdPLA。据报道，AdPLA 参与脂肪分解的局部调节。经测定，AdPLA 表达随禁食而降低，随胰岛素而增加。研究发现，在喂养/胰岛素治疗期间，AdPLA 促进脂肪细胞源性前列腺素 2 (PGE2) 的产生。有人提出，分泌的 PGE2 通过与 G1i 偶联的 EP3 受体结合，通过抑制腺苷酸环化酶和降低 cAMP 水平来抑制脂肪分解。 NRSA 提案中的研究目标是明确 AdPLA-PGE2-EP3 信号在脂肪组织脂解调节中的作用。目标 1 将确定 AdPLA 是否通过脂肪特异性条件敲除小鼠中 PGE2 的产生来抑制脂肪分解。脂肪组织特异性 AdPLA 敲除小鼠将用于实现目标 1。目标 2 将检查体内脂肪组织中 AdPLA 调节脂肪分解是否需要 EP3。 EP3条件敲除小鼠将用于检查目标2。目标3将通过使用AdPLA和EP3条件敲除小鼠以及3T3的原代脂肪细胞，进一步阐明AdPLA-PGE2-EP3途径在体外调节脂肪分解的机制。 -L1学习。必须牢牢理解这一调节，因为它可能为预防和/或治疗 2 型糖尿病等疾病进展提供有益的疗法。 公共卫生相关性：我们社会中肥胖的发生率是显而易见的，并且在过去十年中呈指数级增长。肥胖与寿命缩短以及多种疾病和病症（例如 2 型糖尿病和心脏病）的发生有关。这项研究的目的是了解脂肪组织如何分解甘油三酯，从而帮助其他器官使用脂肪作为燃料。通过了解这一过程，可能会发现增加脂肪使用的可能治疗方法，并可能降低肥胖的患病率。