Metabolite regulation of adipocyte differentiation in obesity

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ABSTRACT The triad of obesity, insulin resistance, and type 2 diabetes mellitus (T2DM) affects roughly 33% of U.S. adults and raises the risk of death from cardiovascular disease. The epidemiological association of obesity with T2DM is unequivocal, but mechanistic links remain unclear. However, it is clear T2DM is distinctly associated with defective fat cell (adipocyte) function, particularly energy storage as lipids and secretion of hormones for systemic insulin sensitivity. We discovered the expression of the enzyme aspartoacylase (ASPA) in white adipose tissue (WAT) correlates with insulin sensitivity in obese subjects. ASPA governs intracellular acetate generation and myelin formation in the brain, but its effect in other tissues remains unknown. This application's overall scientific objective is to unravel how ASPA and acetate contribute to lipid substrates in WAT using well-established in vitro tools and mouse models of obesity. The central hypothesis is that ASPA-derived acetate promotes adipocyte differentiation and systemic energy balance. I will test this hypothesis by pursuing three specific aims: 1) Demonstrate how altered ASPA expression affects lipogenesis in white adipocytes; 2) Define the impact of extracellular acetate on adipogenic competency of precursor cells; 3) Establish the metabolic effects of ASPA disruption in vivo. Mature adipocytes express high ASPA levels and byproducts of ASPA activity flow into lipogenesis, nucleotide biosynthesis, and histone modifications. Therefore, ASPA function likely integrates multiple pathways necessary for adipocytes to overcome nutrient demands in obesity. Lastly, the mentor and training environment will build research and career development skills to realize my ultimate goal of becoming an independent scientist.