Role of adipocyte gene expression regulation by Zfp407 in adipocyte biology and metabolic disease

Zfp407 脂肪细胞基因表达调控在脂肪细胞生物学和代谢疾病中的作用

• 批准号: 9817081
• 负责人: DAVID A BUCHNER
• 金额: $ 40万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9817081
• 关键词: Adipocytes; Adipose tissue; Adult; Binding; Biochemical; Biological Assay; Biology; Cells; ChIP-seq; Clinical; Complement; Complex; DNA; Data; Development; Disease; Fatty acid glycerol esters; Functional disorder; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genomic approach; Health; Insulin; Knock-out; Knockout Mice; Knowledge; Link; Lipids; LoxP-flanked allele; Measures; Mediating; Messenger RNA; Metabolic; Metabolic Diseases; Metabolism; Molecular; Molecular Analysis; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Organism; PPAR gamma; Pathogenesis; Pathway interactions; Physiological; Process; Proteins; RXR; Regulation; Role; Signal Transduction; Site; Stimulus; Structure; Tamoxifen; Techniques; Testing; Therapeutic; Tissues; Transcriptional Regulation; Zinc Fingers; adipocyte biology; adipocyte differentiation; adipokines; base; blood glucose regulation; experimental study; global health; global run on sequencing; glucose uptake; improved; in vivo; insight; insulin sensitivity; knock-down; lipid biosynthesis; lipid metabolism; loss of function; mRNA Stability; metabolic phenotype; new therapeutic target; novel; obesogenic; precursor cell; protein protein interaction; response; small hairpin RNA; transcription factor; transcriptome

Project Summary Adipocytes serve as the body’s primary site for lipid storage and act as signaling centers to coordinate the physiological response to an organism’s nutritional and metabolic state. A better understand of the molecules underlying adipocyte regulation and function will improve our knowledge of the pathophysiology of obesity and type 2 diabetes, which are associated with altered adipocyte function. This proposal will define the metabolic and molecular effects of a poorly understood transcription factor, Zfp407, that was recently identified by our lab as a critical molecule for adipocyte function and insulin sensitivity. We showed that Zfp407 deficiency has broad effects on adipocyte gene expression and results in reduced fat mass, illustrating the critical role of Zfp407 in adipose biology. However, the detailed physiological significance of Zfp407 and cellular mechanisms underlying them remain poorly understood. We propose three Aims to identify the critical physiological role of Zfp407 in differentiating and mature adipocytes and to determine the molecular mechanism by which Zfp407 controls gene expression in adipocytes. In Specific Aim 1, we will discover the physiological function of Zfp407 in mature adipocytes by testing whether constitutive and temporal deletion of Zfp407 in adipocytes alters adipocyte number, survival, and function and determining the metabolic consequences under normal and obesogenic conditions. In Specific Aim 2, we will elucidate the role and mechanism of Zfp407 in the differentiation of white, brown, and beige adipocytes. In Specific Aim 3, we will determine the molecular mechanism by which Zfp407 regulates the adipocyte transcriptome via PPARγ-dependent and PPARγ-independent mechanisms by combining state-of-the-art genomic approaches such as GRO-Seq and BRIC-Seq with classic biochemical techniques. Collectively, these studies will improve our mechanistic understanding of how the regulation of gene expression controls adipocyte differentiation and function. These data will improve our understanding of the pathophysiology of metabolic disease and may identify new translational opportunities for treating obesity and type 2 diabetes.

项目摘要 脂肪细胞充当人体脂质存储的主要位置，并充当信号中心以协调 对生物体营养和代谢状态的物理反应。更好地理解 脂肪细胞调节和功能的基础分子将提高我们对 肥胖症和2型糖尿病的病理生理学，与脂肪细胞功能改变有关。 该建议将定义较知识的转录因子的代谢和分子效应， ZFP407，我们的实验室最近将其确定为脂肪细胞功能和胰岛素的关键分子 灵敏度。我们表明ZFP407缺乏对脂肪细胞基因表达和 导致脂肪质量减少，说明了ZFP407在脂肪生物学中的关键作用。但是， ZFP407的详细生理意义和其基础的细胞机制仍然很差 理解齿。我们提出了三个目的，以确定ZFP407在区分区分中的关键生理作用 和成熟的脂肪细胞，并确定ZFP407控制基因的分子机制 脂肪细胞中的表达。在特定的目标1中，我们将发现ZFP407的物理功能 通过测试脂肪细胞中的宪法和ZFP407的临时删除，成熟的脂肪细胞是否改变了 脂肪细胞数，生存和功能，并确定正常的代谢后果 和肥胖条件。在特定目标2中，我们将阐明ZFP407在 白色，棕色和米色脂肪细胞的分化。在特定目标3中，我们将确定 ZFP407通过PPARγ依赖性调节脂肪细胞转录组的分子机制 通过结合最新基因组方法（例如 带有经典生化技术的gro-seq和金砖四边形。总的来说，这些研究将有所改善 我们对基因表达调节如何控制脂肪细胞如何调节的机械理解 分化和功能。这些数据将提高我们对 代谢疾病，可能会确定治疗肥胖症和类型2的新转化机会 糖尿病。