Metabolite regulation of adipocyte differentiation in obesity

肥胖症脂肪细胞分化的代谢调节

基本信息

批准号：
10387771
负责人：
JESSICA Beserra FELIX
金额：
$ 4.68万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-07 至 2025-02-06
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10387771
关键词：
Acetates Acetyl Coenzyme A Adipocytes Adipose tissue Adult Advanced Development Affect Aspartate Aspartoacylase Biological Assay Brain CRISPR/Cas technology Canavan Disease Cardiovascular Diseases Cells Chronic Citric Acid Cycle Competence Coupled Critical Thinking Data Deposition Differentiated Gene Energy Metabolism Environment Enzymes Epidemiology Experimental Designs Fatty acid glycerol esters Flow Cytometry Gene Expression Generations Genes Goals Growth High Fat Diet Hormone secretion Human Hyperglycemia Hypertrophy In Vitro Inflammation Institution Insulin Resistance Knock-out Knockout Mice Label Learning Link Lipids Liver Mass Spectrum Analysis Medical Mentors Metabolic Metabolism Methods Molecular Morphology Mus Myelin N-acetylaspartate Non-Insulin-Dependent Diabetes Mellitus Nucleotide Biosynthesis Nutrient Obesity Oligodendroglia Outcome Pathway interactions Peripheral Phenotype Physiologic pulse Play Principal Investigator Regulation Research Research Proposals Role Scientist Source Testing Tissues Training Triad Acrylic Resin Volatile Fatty Acids adipocyte differentiation base carbohydrate metabolism career development combat comorbidity defined contribution energy balance extracellular histone modification in vivo insight insulin sensitivity lipid biosynthesis lipid metabolism loss of function mutation metabolic phenotype metabolomics mortality risk mouse model myelin degeneration obese person precursor cell preservation research and development skill acquisition skills therapeutic development tool transcriptome sequencing validation studies

项目摘要

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.

抽象的肥胖、胰岛素抵抗和 2 型糖尿病 (T2DM) 三联症影响着大约 33% 的美国成年人并增加因心血管疾病死亡的风险。肥胖与 T2DM 的流行病学关联是明确的，但机制联系仍不清楚。然而，很明显 T2DM 与脂肪细胞（脂肪细胞）功能有缺陷，特别是脂质能量储存和激素分泌全身胰岛素敏感性。我们发现白色中表达天冬氨酸酰化酶（ASPA）肥胖受试者的脂肪组织（WAT）与胰岛素敏感性相关。 ASPA 控制细胞内醋酸盐大脑中髓磷脂的生成和形成，但其对其他组织的影响仍不清楚。这该应用程序的总体科学目标是揭示 ASPA 和乙酸盐如何影响 WAT 中的脂质底物使用完善的体外工具和肥胖小鼠模型。中心假设是 ASPA 衍生的醋酸盐促进脂肪细胞分化和全身能量平衡。我将通过追求来检验这个假设三个具体目标：1) 展示 ASPA 表达的改变如何影响白色脂肪细胞的脂肪生成； 2) 明确细胞外乙酸盐对前体细胞成脂能力的影响； 3）建立 ASPA 破坏体内代谢的影响。成熟脂肪细胞表达高 ASPA 水平和副产物 ASPA 活性涉及脂肪生成、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营养需求所需的多种途径。最后，导师和培训环境将培养研究和职业发展技能，以实现我的最终目标成为一名独立科学家。