Metabolite regulation of adipocyte differentiation in obesity

摘要 肥胖、胰岛素抵抗和2型糖尿病（T2 DM）三联征影响着大约33%的美国成年人 并增加了死于心血管疾病的风险。肥胖与T2 DM的流行病学关联 是明确的，但机械联系仍然不清楚。然而，很明显，T2 DM与以下因素明显相关： 缺陷的脂肪细胞（脂肪细胞）功能，特别是作为脂质的能量储存和激素分泌， 全身胰岛素敏感性我们在白色中发现了酶乙酰化酶（ASPA）的表达， 脂肪组织（WAT）与肥胖受试者的胰岛素敏感性相关。ASPA控制细胞内乙酸盐 在脑中，它可以促进髓鞘的生成和髓鞘的形成，但它在其他组织中的作用仍然未知。这 应用程序的总体科学目标是揭示ASPA和乙酸盐如何在WAT中对脂质底物起作用 使用成熟的体外工具和肥胖小鼠模型。核心假设是ASPA衍生的 乙酸促进脂肪细胞分化和全身能量平衡。我将通过追踪 三个具体目标：1）证明改变的ASPA表达如何影响白色脂肪细胞中的脂肪生成; 2)确定细胞外乙酸盐对前体细胞成脂能力的影响; 3）建立细胞外乙酸盐对前体细胞成脂能力的影响。 ASPA破坏对体内代谢的影响。成熟的脂肪细胞表达高水平的ASPA， ASPA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症营养需求所必需的多种途径。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.