Secretory phospholipase A2 enhances metabolic rate

分泌型磷脂酶 A2 提高代谢率

• 批准号: 10012457
• 负责人: Edwards A Park
• 金额: --
• 依托单位: MEMPHIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012457
• 关键词: Adipocytes; Adipose tissue; Adsorption; Aging; Americas; Anti-Bacterial Agents; Atherosclerosis; Bacterial Infections; Basic Science; Body Weight decreased; Brown Fat; C57BL/6 Mouse; Calcium; Cardiovascular Diseases; Cardiovascular system; Clinical; Complications of Diabetes Mellitus; Data; Diabetes Mellitus; Diet; Disease Resistance; Eicosanoids; Elements; Energy Metabolism; Enzymes; Exons; Expression Profiling; Family; Family member; Fatty Acids; Fatty acid glycerol esters; Frameshift Mutation; Gene Expression; Genes; Glucocorticoids; Glycerophospholipids; Health; High Fat Diet; Hormones; Human; Hyperlipidemia; Inbred BALB C Mice; Inflammation; Inflammatory Response; Insulin; Insulin Resistance; Intestines; Investigation; Knock-out; Laboratories; Link; Lipids; Lysophospholipids; Mediating; Medical; Membrane; Metabolic; Metabolic Activation; Metabolic Diseases; Metabolic syndrome; Metabolism; Mitochondria; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nuclear; Obesity; PLA2G2A gene; Pathologic Processes; Patients; Phosphatidylethanolamine; Phosphatidylserines; Phospholipase; Phospholipase A2; Phospholipids; Phosphotransferases; Physiological Processes; Population; Positioning Attribute; Protein Isoforms; Proteins; Regulatory Pathway; Resistance; Risk Factors; Role; Signal Transduction; Signaling Molecule; Stroke; Testing; Therapeutic Intervention; Tissues; Veterans; Weight Gain; Work; clinically relevant; combat; cytokine; glucose tolerance; improved; insight; insulin sensitivity; insulin sensitizing drugs; lipid mediator; member; metabolic rate; mitochondrial metabolism; novel; oxidized low density lipoprotein; uncoupling protein 1

Obesity and the ensuing cardiovascular and diabetic complications are a major medical concern in the Veteran population as approximately 35-40 percent of the Veterans are classified as obese. Activation of brown adipose tissue (BAT) and the browning of white adipose tissue are among the many strategies under consideration for weight loss and improvement of insulin sensitivity. Secretory phospholipase A2 group IIa (PLA2G2A) has been studied with respect to inflammation and anti-bacterial actions. However, the role of this phospholipase in metabolism is not known and that has been the subject of our recent investigations. PLA2G2A is a member of a large family of secretory phospholipases (sPLA2). PLA2G2A hydrolyzes fatty acid molecules from the sn-2 position of membrane glycerophospholipids to release a free fatty acid and a lysophospholipid. We have used C57BL/6 mice expressing the human PLA2G2A gene as a model to explore the impact of PLA2G2A on metabolism. Surprisingly, we discovered that the mice expressing PLA2G2A were resistant to weight gain when fed a high fat diet and remained highly insulin sensitive. In addition, these mice had an elevated metabolic rate due to the activation of uncoupling protein 1 (Ucp1) in brown adipose tissue (BAT). In this application, we will investigate the mechanisms by which PLA2G2A promotes mitochondrial uncoupling in BAT and enhances insulin sensitivity. Our overall hypothesis is that PLA2G2A generates eicosanoids or lysophospholipids which enhance BAT mitochondrial uncoupling in human and mouse brown adipocytes. We propose to determine the impact of BAT specific expression of PLA2G2A and Pla2g2a knockout on metabolic rate and insulin sensitivity. We will identify the lipid mediators generated by PLA2G2A and determine their role in BAT metabolism. Finally, we will delineate the signaling mechanisms by which PLA2G2A activates BAT. These studies are very novel as few studies have been conducted on the contribution of any secretory PLA2 family member to energy expenditure. We will define new regulatory pathways in brown adipose tissue metabolism. The proposed work will have a high impact since elevating the metabolic rate has great potential to reduce obesity, cardiovascular disease and insulin resistance. These are conditions commonly found in aging Veterans.

肥胖和随之而来的心血管和糖尿病并发症是美国的主要医学问题。 退伍军人人口约35- 40%的退伍军人被列为肥胖。激活 褐色脂肪组织（BAT）和白色脂肪组织的布朗宁是许多策略中的一种 正在考虑减肥和改善胰岛素敏感性。分泌型磷脂酶A2 IIa组（PLA 2G 2A）的炎症和抗菌作用已经被研究。然而，在这方面， 这种磷脂酶在代谢中的作用尚不清楚，这是我们最近研究的主题。 调查事务所PLA 2G 2A是分泌型磷脂酶（sPLA 2）大家族的成员。PLA2g2a 从膜甘油磷脂的sn-2位水解脂肪酸分子， 脂肪酸和溶血磷脂。我们使用表达人PLA 2G 2A基因的C57 BL/6小鼠作为研究对象。 探索PLA 2G 2A对代谢的影响的模型。令人惊讶的是，我们发现， 表达PLA 2G 2A的小鼠在喂食高脂饮食时抵抗体重增加，并保持高胰岛素水平。 敏感此外，由于解偶联蛋白的激活，这些小鼠的代谢率升高 1（Ucp 1）在棕色脂肪组织（BAT）。在这个应用程序中，我们将调查的机制， PLA 2G 2A促进BAT中的线粒体解偶联并增强胰岛素敏感性。我们的整体 假设是PLA 2G 2 A产生类二十烷酸或溶血磷脂，从而增强BAT 人和小鼠棕色脂肪细胞的线粒体解偶联。我们建议确定 BAT特异性表达PLA 2g 2A和PLA 2g 2a敲除对代谢率和胰岛素敏感性的影响我们 将确定由PLA 2G 2A产生的脂质介质，并确定它们在BAT代谢中的作用。最后， 我们将描述PLA 2G 2A激活BAT的信号机制。这些研究非常 很少有关于任何分泌型PLA 2家族成员对 能量消耗我们将确定新的监管途径在棕色脂肪组织代谢。的 拟议的工作将有很大的影响，因为提高代谢率有很大的潜力， 肥胖、心血管疾病和胰岛素抵抗。这些都是常见的条件在老化 老兵