Secretory phospholipase A2 enhances metabolic rate

分泌型磷脂酶 A2 提高代谢率

• 批准号: 10164563
• 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/10164563
• 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; Disease Resistance; Eicosanoids; Elements; Energy Metabolism; Enzymes; Exons; 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; 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; cytokine; diet-induced obesity; glucose tolerance; improved; insight; insulin sensitivity; insulin sensitizing drugs; lipid mediator; lipidomics; member; metabolic rate; military veteran; 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