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/总结 棕色脂肪组织 (BAT) 通过称为适应性的过程消耗能量的能力 生热作用使其成为干预肥胖的有吸引力的目标；然而，观察到 BAT 质量 人类肥胖的减少引起了人们对其完全激活后在临床上影响体重的能力的担忧。 然而，储存能量的白色脂肪组织（WAT）也可以采用“棕色”的产热表型； 是对白色脂肪细胞中产热基因程序的有效分子制动器，有助于维持其能量- 由于 WAT 的质量远大于 BAT，因此产热基因被激活。 白色脂肪细胞的计划可能是干预肥胖的更可行的策略，但是其机制； 控制能量燃烧与能量储存脂肪细胞谱系的建立和维持 保持未定义。 ZFP423是锌指蛋白C2H2家族的成员，是一种生理调节转录 通过抑制生热来维持白色脂肪细胞能量储存表型的因子 棕色/米色脂肪细胞的基因程序特征与棕色脂肪细胞发生物理相互作用。 白色脂肪细胞中的决定因子 EBF2 可防止 EBF2 依赖性染色质重塑和 PPARg 占据关键产热基因。 我打算在杜克大学医学博士培训期间进行的实验 科学家培训计划将利用生物化学、分子生物学和小鼠方面的先进方法 这项工作是在杜克大学分子生理学系的 Rana Gupta 博士的指导下进行的。 研究所，旨在 1) 解决 ZFP423 直接招募 NuRD 复合物的能力这一假设 EBF2 对于其抑制白色脂肪细胞产热的能力至关重要 (Aim1)，并且 2) 测试 假设小鼠中 ZFP423-EBF 复合物的基因破坏足以允许产热 WAT 我提出的总体目标是重塑和预防肥胖和代谢功能障碍的发展。 研究的目的是进一步确定导致产热抑制的关键蛋白质-蛋白质相互作用 ZFP423 在白色脂肪细胞中的基因程序的成功完成将凸显这项工作的重要性。 脂肪细胞中产热基因表达的转录“刹车”，可能会提出一种解锁策略 WAT 促进减肥和/或改善营养稳态的生热能力。