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

项目摘要 脂肪细胞是人体储存脂肪的主要场所，并作为信号中心协调 对有机体的营养和代谢状态的生理反应。更好地理解 脂肪细胞调节和功能的潜在分子将提高我们对 肥胖和2型糖尿病的病理生理学，这与脂肪细胞功能改变有关。 这一提议将定义一种鲜为人知的转录因子的代谢和分子效应， Zfp407，最近被我们的实验室鉴定为脂肪细胞功能和胰岛素的关键分子 敏感度。我们发现Zfp407缺乏对脂肪细胞的基因表达有广泛的影响 结果减少了脂肪质量，说明了Zfp407在脂肪生物学中的关键作用。然而， Zfp407的详细生理意义及其背后的细胞机制尚不清楚 明白了。我们提出了三个目标来确定Zfp407在分化中的关键生理作用 和成熟脂肪细胞，并确定Zfp407控制基因的分子机制 在脂肪细胞中表达。在特定的目标1中，我们将发现Zfp407在 通过检测脂肪细胞中Zfp407的结构性和时间性缺失是否改变成熟脂肪细胞 正常情况下脂肪细胞的数量、存活和功能及其代谢结果的决定 以及肥胖症。在特定的目标2中，我们将阐明Zfp407在 白色、棕色和米色脂肪细胞的分化。在具体目标3中，我们将确定 Zfp407通过依赖PPARγ调控脂肪细胞转录组的分子机制 和PPARγ无关的机制，通过结合最先进的基因组方法，如 Gro-Seq和BRIC-Seq采用经典的生化技术。总体而言，这些研究将有所改善 我们对基因表达调控如何控制脂肪细胞的机械理解 分化和功能。这些数据将提高我们对糖尿病的病理生理学的理解。 代谢性疾病，并可能发现治疗肥胖症和2型的新的翻译机会 糖尿病。

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.