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.
Obesity is very prevalent in America today and occurs in 40% of our Veterans. Obesity worsens many aspects of cardiovascular disease by increasing insulin resistance, hyperlipidemia and atherosclerosis. One strategy for promoting weight loss is to increase energy expenditure by activating brown adipose tissue. Brown adipose tissue metabolizes fat to generate heat rather than usable energy. We have discovered a secretory phospholipase that activates brown adipose tissue. We propose to further define the novel role of this phospholipase. We will discover the mechanisms underlying the activation of brown adipose tissue and determine how this secretory phospholipase improves insulin sensitivity. Answering these questions will suggest strategies for altering adipose tissue metabolism and improving insulin responsiveness. These are issues directly related to type 2 diabetes and obesity, two common concerns of Veterans health. 1
