Cellular and molecular mechanisms by which fatty acids regulate adipocyte metabolism

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The goal of this research proposal is to investigate the fundamental mechanisms by which stearoyl-CoA desaturase (SCD) and monounsaturated fatty acids (MUFA) regulate adipocyte metabolism. The adipocyte is a cell that contributes to the regulation of whole-body metabolism by: 1) secreting factors that influence a wide range of biological functions, including energy homeostasis, metabolism, and insulin sensitivity, and 2) storing excess energy in the form of triglycerides. One class of compounds that has garnered considerable interest recently are MUFA, which are key substrates in the formation of phospholipids, triglycerides, and cholesterol esters. In addition to being amongst the principle fatty acids consumed in the diet, MUFA are also synthesized de novo by SCD. Although no structural differences exist between dietary and de novo synthesized MUFA, an intriguing paradox has emerged. The increased consumption of dietary MUFA is associated with weight loss and improved blood pressure, plasma lipid profiles, and glycemic control; however, conversely, a high SCD activity that increases de novo MUFA production is related to lipid accumulation, insulin resistance, and obesity. This research proposal aims to address this paradox using a combination of cell biology, metabolite profiling, gene silencing, and bioinformatic technologies. Metabolites will be measured with mass spectrometry in differentiating human adipocytes, i.e. the conversion from premature adipocyte to lipid-engorged adipocyte. Inhibiting SCD gene expression will diminish de novo MUFA synthesis; thereby highlighting the role of SCD on adipocyte cell metabolism. Additionally, SCD-depleted cells will be independently treated with various fatty acids in order to determine whether extracellular MUFA are processed differently by adipocytes. Taken together, the results generated during this research proposal will provide novel insight regarding the role of SCD on adipocyte metabolism, as well as take an important first step towards resolving the MUFA paradox. Additionally, this research will have a long-term impact in the scientific community by improving our understanding of the role of adipocytes in whole-body metabolism.