Metabolite regulation of adipocyte differentiation in obesity

摘要 肥胖、胰岛素抵抗和2型糖尿病(T2 DM)这三个因素影响着大约33%的美国成年人 并增加了死于心血管疾病的风险。肥胖与2型糖尿病的流行病学相关性研究 是明确的，但机械性的联系仍然不清楚。然而，很明显，T2 DM与 脂肪细胞(脂肪细胞)功能有缺陷，特别是作为脂类的能量储存和激素的分泌 全身性胰岛素敏感性。我们发现了天冬氨酸氨基转移酶(ASPA)在白色 肥胖者的脂肪组织(WAT)与胰岛素敏感性相关。ASPA控制细胞内醋酸酯 在大脑中产生和形成髓鞘，但它在其他组织中的作用尚不清楚。这 应用程序的总体科学目标是解开ASPA和醋酸酯对水中脂肪底物的贡献 使用成熟的体外工具和肥胖的小鼠模型。中心假设是ASPA派生的 醋酸盐促进脂肪细胞分化和全身能量平衡。我将通过以下方式来验证这一假设 三个具体目标：1)证明ASPA表达的改变如何影响白色脂肪细胞的脂肪生成； 2)明确细胞外醋酸酯对前体细胞成脂能力的影响；3)建立 ASPA干扰对体内代谢的影响。成熟脂肪细胞表达高水平的ASPA及其副产物 天冬氨酸氨基转移酶活性流入脂肪生成、核苷酸生物合成和组蛋白修饰。因此，ASPA功能 可能整合了脂肪细胞克服肥胖时的营养需求所需的多种途径。最后， 导师和培训环境将建立研究和职业发展技能，以实现我的最终目标 成为一名独立的科学家。

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.