ROLE OF THE MONOACYLGLYCEROL ACYLTRANSFERASE PATHWAY IN ADIPOSE TISSUE TRIGLYCERIDE METABOLISM

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ABSTRACT The number of obese individuals worldwide has reached epidemic proportions and is a major global health concern. Excessive adipose tissue stores predispose individuals to developing type 2 diabetes, hypertension, coronary heart disease, stroke, fatty liver disease, dementia, obstructive sleep apnea and many types of cancer. Adipose tissue acts as the master regulator of lipid storage, and through secretion of adipokines, influences many systemic processes, including energy metabolism, inflammation, and pathophysiological changes associated with disease. A more thorough understanding of the pathways that regulate triglyceride synthesis and storage is necessary for the development of new effective therapeutic treatments of obesity. There are two independent, but convergent pathways for triglyceride biosynthesis. The glycerol-3-phosphate (G3P) pathway or Kennedy pathway is considered the predominant pathway in most cell types. The alternative pathway for triglyceride biosynthesis, known as monoacylglycerol acyltransferase (MGAT) pathway has been most extensively characterized in intestinal enterocytes where it is involved in dietary fat absorption. This application is designed to test the novel and innovative hypotheses that the MGAT pathway of triglyceride synthesis is important for controlling lipid metabolism in adipose tissue and that perturbations in this pathway affect adipose tissue triglyceride synthesis and metabolism. We have postulated that MGAT activity facilitates incorporation of lipid into its preferred and inert storage form in adipocytes and prevents free fatty acids from entering circulation. The studies proposed herein are designed to: [1] define the role that MGAT activity plays in adipocyte triglyceride metabolism, [2] to examine the role of adipose tissue MGAT1 in states associated with increased lipolysis, and [3] to test the role MGAT1 in regulating adipocyte and whole body lipid metabolism by an in vivo loss-of-function approach. The results of these studies will not only have implications for our understanding of the biology of MGAT proteins, but will also provide new insight into the basic molecular regulation of monoacylglycerol and FFA metabolism in adipose tissue. More importantly, modulation of MGAT1 expression and activity in adipose tissue may represent a novel and effective treatment of obesity.