Elucidating the Transcriptional Brakes on Adipocyte Thermogenesis

阐明脂肪细胞产热的转录制动

• 批准号: 10669395
• 负责人: Ashley T Truong
• 金额: $ 5.27万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-06 至 2028-04-05
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10669395
• 关键词: Address; Adipocytes; Adipose tissue; Adopted; Biochemistry; Body Weight; Body Weight decreased; Brown Fat; Characteristics; Clinical; Complex; Disease; Doctor of Philosophy; Energy Intake; Energy Metabolism; Family; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Homeostasis; Human; Intervention; Maintenance; Medical; Mentorship; Metabolic dysfunction; Molecular; Molecular Biology; Mus; NuRD complex; Nutrient; Obesity; Phenotype; Physiological; Physiology; Process; Proteins; Rana; Research; Scientist; Testing; Therapeutic; Thermogenesis; Training; Training Programs; Triglycerides; Universities; Work; Zinc Fingers; chromatin remodeling; design; energy balance; experimental study; improved; member; mouse genetics; obesity development; prevent; programs; protein protein interaction; recruit; transcription factor

PROJECT ABSTRACT/SUMMARY The ability of brown adipose tissue (BAT) to expend energy through a process called adaptive thermogenesis makes it an attractive target for intervention in obesity; however, the observation that BAT mass diminishes in human obesity raises concerns about its ability to clinically impact body weight when fully activated. Energy-storing white adipose tissue (WAT) can also adopt a “brown-like” thermogenic phenotype; however, there are potent molecular brakes on thermogenic gene program in white adipocytes that help maintain its energy- storing phenotype. Since WAT is present in far greater mass than BAT, activation of the thermogenic gene program in white adipocytes may be a more viable strategy for intervention in obesity; however, the mechanisms controlling the establishment and maintenance of the energy-burning vs. energy-storing adipocyte lineages remain undefined. ZFP423, a member of the C2H2 family of zinc finger proteins, is a physiologically regulated transcription factor that functions to maintain the energy-storing white adipocyte phenotype by suppressing the thermogenic gene program characteristic of brown/beige fat cells. ZFP423 physically interacts with the brown adipocyte determination factor, EBF2, in white adipocytes to prevent EBF2-dependent chromatin remodeling and PPARg occupancy at key thermogenic genes. The experiments that I propose to conduct as part of my PhD training in the Duke University Medical Scientist Training Program will utilize advanced approaches in biochemistry, molecular biology, and mouse genetics. This work, conducted under the mentorship of Dr. Rana Gupta at the Duke Molecular Physiology Institute, is designed to 1) address the hypothesis that the ability of ZFP423 to directly recruit the NuRD complex to EBF2 is essential for its ability to suppress thermogenesis in white adipocytes (Aim1), and 2) test the hypothesis that genetic disruption of the ZFP423-EBF complex in mice is sufficient to permit thermogenic WAT remodeling and prevent the development of obesity and metabolic dysfunction. The overall goal of my proposed research is to further define the critical protein-protein interactions leading to the suppression of the thermogenic gene program by ZFP423 in white adipocytes. Successful completion of this work will highlight the importance of transcriptional “brakes” on thermogenic gene expression in adipocytes and may suggest a strategy to unlock the thermogenic capacity of WAT to promote weight loss and/or improve nutrient homeostasis.

项目摘要/摘要 棕色脂肪组织（BAT）通过称为自适应的过程探索能量的能力 热发生使其成为干预肥胖症的吸引力。但是，观察到蝙蝠质量 人类肥胖症的减少引起了人们对其在充分激活时影响体重的能力的担忧。 能量存储白色脂肪组织（WAT）也可以采用“棕色”的热表型。但是，那里 是白色脂肪细胞中热基因程序的潜在分子制动器，有助于维持其能量 - 存储表型。由于WAT的质量比BAT大得多，因此热基因的激活 白色脂肪细胞中的程序可能是干预肥胖症的更可行的策略；但是，机制 控制能量燃烧与能量存储脂肪细胞谱系的建立和维护 保持不确定。 ZFP423是锌指蛋白的C2H2家族的成员，是一种物理调节的转录 通过抑制热源性来维持能量存储能量的白脂肪细胞表型的因素 棕色/米色脂肪细胞的基因程序特征。 ZFP423与棕色脂肪细胞物理相互作用 确定因子EBF2，在白色脂肪细胞中，以防止EBF2依赖性染色质重塑和PPARG 关键热基因的占用率。 我建议在杜克大学医学博士培训的一部分中进行的实验 科学家培训计划将利用生物化学，分子生物学和小鼠的先进方法 遗传学。这项工作，在杜克分子生理学的Rana Gupta博士的心态下进行 研究所旨在1）解决以下假设：ZFP423直接招募Nurd Complex的能力 到EBF2对于抑制白脂肪细胞中的热生成的能力至关重要（AIM1），并且2）测试 假设小鼠中ZFP423-EBF复合物的遗传破坏足以允许热水 重塑并防止肥胖和代谢功能障碍的发展。我的提议的总体目标 研究是为了进一步定义临界蛋白质蛋白质相互作用，导致热抑制 ZFP423的基因程序在白色脂肪细胞中。成功完成这项工作将突出重要性 在脂肪细胞中热基因表达上的转录“制动器”，并可能提出解锁策略 WAT的热能能力促进体重减轻和/或改善营养稳态。