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.
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.
