Secretory phospholipase A2 enhances metabolic rate

肥胖以及随之而来的心血管和糖尿病并发症是 退伍军人人口约有35%-40%的退伍军人被归类为肥胖。激活 棕色脂肪组织(BAT)和白色脂肪组织的褐化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(Pla2g2a)已被研究在炎症和抗菌作用方面。然而， 这种磷脂酶在新陈代谢中的作用尚不清楚，这是我们最近研究的主题 调查。Pla2g2a是分泌型磷脂酶(SPLA2)大家族的成员。Pla2g2a 水解膜甘油磷脂sn-2位的脂肪酸分子以释放游离的 脂肪酸和一种溶血磷脂。我们已经用表达人Pla2g2a基因的C57BL/6小鼠作为 探讨Pla2g2a对代谢影响的模型。令人惊讶的是，我们发现这些老鼠 表达Pla2g2a的人在高脂肪饮食中抵抗体重增加，并保持高胰岛素水平 很敏感。此外，由于解偶联蛋白的激活，这些小鼠的代谢率提高。 1(Ucp1)在棕色脂肪组织(BAT)。在本应用程序中，我们将研究 Pla2g2a促进BAT线粒体解偶联，增强胰岛素敏感性。我们的整体 假说是，Pla2g2a产生二十烷基类化合物或溶血磷脂，从而增强BAT 人和小鼠棕色脂肪细胞线粒体解偶联。我们建议确定以下因素的影响 BAT特异性表达Pla2g2a和Pla2g2a基因敲除对代谢率和胰岛素敏感性的影响我们 将确定由Pla2g2a产生的脂质介质，并确定它们在BAT新陈代谢中的作用。最后， 我们将描述Pla2g2a激活BAT的信号机制。这些研究是非常 新的，因为很少有研究对任何分泌的PLA2家族成员对 能源支出。我们将在棕色脂肪组织代谢中定义新的调控途径。这个 拟议的工作将产生很大的影响，因为提高代谢率有很大的潜力降低 肥胖、心血管疾病和胰岛素抵抗。这些都是衰老中常见的情况。 退伍军人。

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.