Grant: Operating Grant

Triacylglycerol (TG) is the major source of stored energy in humans. However, excessive accumulation of TG in tissues can lead to obesity, diabetes and heart disease. Obesity has now reached epidemic proportions in Canada with 25% of the Canadian population now considered obese, while 60% are considered overweight. In the last 20 years, deaths attributable to complications from obesity have doubled and billions of dollars per year are spent on health care costs that are attributable to obesity. Clearly mechanisms to prevent the excess accumulation of TG would be extremely important for controlling obesity and related diseases. Our laboratory is focused on studying the mechanisms of TG synthesis in fat cells (adipocytes). Two proteins, diacylglycerol acyltransferase-1 (DGAT1) and diacylglycerol acyltransferase-2 (DGAT2) are responsible for producing TG in mammals. Numerous studies have shown that these two enzymes have important but distinct roles in TG metabolism and that DGAT2 is responsible for producing the majority of TG. The main objective of this study is to investigate the cellular and molecular processes in adipocytes that are required for DGAT2 to synthesize TG. Specific areas that we intend to focus on include determining if the efficient synthesis of TG is dependent on the interaction of DGAT2 with other proteins or on its specific location within a cell. We also will determine if TG levels can be controlled by modulating the degradation rate of DGAT2 to increase or decrease TG synthesis. DGAT2 represents an ideal potential drug target for developing inhibitors to treat obesity and related metabolic disorders. By understanding how this enzyme works in cells to produce TG, we can generate information that may be useful for developing effective treatment strategies for human diseases.