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)通过一种称为适应性的过程消耗能量的能力 产热作用使其成为干预肥胖的一个有吸引力的目标；然而，观察到蝙蝠的质量 人类肥胖的减少引起了人们对其在完全激活时临床上影响体重的能力的担忧。 储能的白色脂肪组织(Wat)也可以表现为“棕色样”的产热表型；然而， 是白色脂肪细胞中产热基因程序的有效分子刹车，有助于维持其能量- 储存表型。由于Wat的质量比BAT大得多，因此致热基因的激活 白色脂肪细胞计划可能是干预肥胖的更可行的策略；然而，其机制 控制能量燃烧与能量储存脂肪细胞系的建立和维持 仍然没有定义。 ZFP423是锌指蛋白C2H2家族中的一员，是一种生理调节转录 通过抑制产热来维持储能白色脂肪细胞表型的因子 棕色/米色脂肪细胞的基因程序特征。ZFP423与棕色脂肪细胞发生物理相互作用 白色脂肪细胞中阻止Ebf2依赖的染色质重塑和PPARg的决定因子Ebf2 关键致热基因的占有率。 作为我在杜克大学医学院博士培训的一部分，我计划进行的实验 科学家培训计划将利用生物化学、分子生物学和老鼠方面的先进方法 遗传学。这项工作是在杜克大学分子生理学的拉纳·古普塔博士的指导下进行的 旨在1)解决ZFP 423直接招募NuRD复合体的能力这一假设 Ebf2对于其抑制白色脂肪细胞产热的能力(Aim1)是必不可少的，2)测试 假设ZFP423-EBF复合体在小鼠中的遗传破坏足以允许生热水 重塑和预防肥胖和代谢功能障碍的发展。我提议的总体目标是 研究是进一步定义导致生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编程。这项工作的成功完成将突出这一重要性 对脂肪细胞中产热基因表达的转录“刹车”，并可能提出一种解锁策略 Wat促进减肥和/或改善营养动态平衡的生热能力。