权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Characterizing the mechanisms controlling the rate of adipogenesis in vitro and in vivo

表征体外和体内控制脂肪生成速率的机制

基本信息

批准号：
317440205
负责人：
Dr. Stefan Tholen
金额：
--
依托单位：
Department of Chemical and Systems Biology
依托单位国家：
德国
项目类别：
Research Fellowships
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/317440205?language=en
关键词：
Characterizing mechanisms controlling rate adipogenesis

项目摘要

Obesity constitutes a public health problem and enhances the risk for cardiovascular disease and metabolic disorders such as insulin resistance. Since adipose tissue is essential for the homeostatic control of metabolism, dysregulated expansion of adipose tissue affects the whole body. In obesity fat depots increase by differentiation of fat cells in a process called adipogenesis. Detailed understanding of the regulatory circuits underlying adipogenesis is missing and could enable to find ways to therapeutically control growth of adipose tissue in pathological conditions. Upon healthy conditions tissue size is preserved by balancing cell proliferation, differentiation and cell death. Hence, adipocytes renew in the human body at a rate of 10% per year. As all preadipocytes in the human body are subjected to the same differentiation stimuli it remains elusive why not the whole population of proliferating preadipocytes differentiates into non-dividing and lipid accumulating adipocytes. The laboratory of Dr. Mary Teruel addressed this question and realized that adipogenesis is controlled by a highly dynamic and interconnected regulatory network. They developed unique single cell imaging techniques, computational modeling, and targeted proteomics approaches, which revealed that preadipocytes in cell culture differentiate into terminal non-dividing adipocytes through an all-or-none, bistable switch mechanism, which is driven by seven feedback loops between critical regulator proteins and PPARgamma, the master transcriptional regulator of adipocyte differentiation. This regulatory network coupled with variation in protein expression provides a tunable system to maintain low rates of terminal adipocyte differentiation. This project aims to prove that this ultra-high feedback loop architecture is relevant in vivo. In my experimental strategy, I will employ the AdipoChaser mouse model which allows determining the exact timeframe of de novo adipogenesis by permanent labeling of mature adipocytes. I will investigate in vivo relevant feedback regulators in terms of timing, sequential order, and connectivity in following cell culture experiments. To evaluate how expression levels and timing of the feedback regulator proteins affect rates of adipogenesis upon physiological stimuli, I will apply gain and loss of function strategies of different feedback mediators in allograft models to quantitate differentiation rates in vivo. Results from this study will highlight which feedback mediators are essential to keep adipocyte differentiation rates low and thus, at least in part, answer the key question how organisms maintain adipose tissue size. In addition this study will provide a better understanding of the regulatory mechanism underlying adipogenesis, which may contribute to attempts to therapeutically control adipogenesis in metabolic disease.

肥胖构成了一个公共卫生问题，并增加了心血管疾病和胰岛素抵抗等代谢紊乱的风险。由于脂肪组织对于代谢的稳态控制是必不可少的，因此脂肪组织的失调扩张影响整个身体。在肥胖症中，脂肪库通过脂肪细胞的分化而增加，这一过程称为脂肪形成。缺乏对脂肪形成的调控回路的详细了解，这可能有助于找到在病理条件下治疗性控制脂肪组织生长的方法。在健康条件下，通过平衡细胞增殖、分化和细胞死亡来保持组织大小。因此，脂肪细胞在人体内以每年10%的速度更新。由于人体内所有的前脂肪细胞都受到相同的分化刺激，因此仍然难以理解为什么增殖的前脂肪细胞的整个群体不能分化成非分裂和脂质积累的脂肪细胞。玛丽特鲁埃尔博士的实验室解决了这个问题，并意识到脂肪形成是由一个高度动态和相互关联的调控网络控制的。他们开发了独特的单细胞成像技术，计算建模和靶向蛋白质组学方法，这些方法揭示了细胞培养中的前脂肪细胞通过全或无的开关机制分化为末端非分裂脂肪细胞，该机制由关键调节蛋白和PPARgamma之间的七个反馈回路驱动，PPARgamma是脂肪细胞分化的主要转录调节因子。这种调控网络与蛋白质表达的变化相结合，提供了一个可调系统，以维持低的终末脂肪细胞分化率。该项目旨在证明这种超高反馈回路架构与体内相关。在我的实验策略中，我将采用AdipoChaser小鼠模型，该模型允许通过永久标记成熟脂肪细胞来确定从头脂肪形成的确切时间范围。在接下来的细胞培养实验中，我将研究体内相关的反馈调节器在时间，顺序和连接方面的作用。为了评估反馈调节蛋白的表达水平和时间如何影响生理刺激后的脂肪形成速率，我将在同种异体移植模型中应用不同反馈介质的功能获得和丧失策略来定量体内分化率。这项研究的结果将突出哪些反馈介质是保持脂肪细胞分化率低所必需的，从而至少部分回答了生物体如何保持脂肪组织大小的关键问题。此外，这项研究将提供一个更好的了解的调节机制，脂肪生成的基础上，这可能有助于尝试治疗控制脂肪代谢疾病。