Recruitment of brown adipocytes in visceral white adipose tissue by fibroblast growth factor 8b

成纤维细胞生长因子 8b 将棕色脂肪细胞募集到内脏白色脂肪组织中

• 批准号: 321208980
• 负责人: Privatdozent Dr. Tobias Fromme
• 金额: --
• 依托单位: Lehrstuhl für Klinische Ernährungsmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/321208980?language=en
• 关键词: Recruitment; brown; adipocytes; visceral; white

Brown adipose tissue (BAT) is an organ equipping mammals with a means of non-shivering thermogenesis. In brown adipocyte mitochondria, uncoupling protein 1 (Ucp1) allows re-entry of protons from the intermembrane space into the matrix bypassing ATP synthase and thus uncoupling oxygen consumption from ATP production. By this mechanism, energy stored in the form of proton motive force is released as heat. Brown adipocytes are not restricted to uniform, classical BAT depots but are often found interspersed in white adipose tissue depots. In an ongoing grant project we study the ability of fibroblast growth factor 8b to recruit Ucp1 expressing cells within white adipose tissue. A major results was the identification of preadipocytes, not mature adipocytes, as the source of detected Ucp1 transcript and protein. To our knowledge, this is the first published observation of Ucp1 expression prior to terminal differentiation in the preadipocytes/adipocyte lineage and constitutes a unique opportunity to identify and study highly Ucp1-specific transcriptional regulators that are not part of the general brown adipogenesis transcriptional machinery.We here propose to obtain a comprehensive understanding of this model system on the regulatory, transcriptional and metabolic level. On this basis, it can be employed to study the specific components of Ucp1 expression control outside the classical adipogenesis/ mitogenesis clusters of transcription factors. We thus aim to fully elucidate all links of signal transduction from the already identified receptor to the Ucp1 gene promotor and enhancer. One important aspect will be the role of lactate that is abundantly produced by preadipocytes in response to Fgf8b and that at the same time amplifies Fgf8b action on the Ucp1 promotor. A thorough investigation of the metabolic phenotype and morphology of Fgf8b-recruited cells will be complemented by ongoing transcriptome analyses to fully characterize this uniquely Ucp1-expressing cell type.In summary, we propose to gain an in-depth understanding of the cellular identity of former white and brown preadipocytes driven to express Ucp1 in response to Fgf8b treatment. The resulting, highly unusual cells will serve as a key to understand specific transcriptional regulation of the Ucp1 gene outside of the canonical adipogenic/ mitogenic transcription factor network currently understood to dominate the entire transcript signature of brown adipocytes.

褐色脂肪组织（BAT）是哺乳动物具有非寒颤产热能力的器官。在棕色脂肪细胞线粒体中，解偶联蛋白1 （Ucp1）允许质子从膜间空间重新进入基质，绕过ATP合酶，从而从ATP生产中解偶联耗氧。通过这种机制，以质子动力形式储存的能量以热的形式释放出来。棕色脂肪细胞并不局限于均匀的，经典的BAT仓库，但经常发现穿插在白色脂肪组织仓库。在一个正在进行的资助项目中，我们研究了成纤维细胞生长因子8b招募白色脂肪组织中表达Ucp1的细胞的能力。一个主要的结果是鉴定了前脂肪细胞，而不是成熟脂肪细胞，作为检测到的Ucp1转录物和蛋白的来源。据我们所知，这是首次发表的对前脂肪细胞/脂肪细胞谱系终末分化前Ucp1表达的观察，并为鉴定和研究不属于一般棕色脂肪形成转录机制的高度Ucp1特异性转录调节因子提供了独特的机会。在此，我们建议从调控、转录和代谢水平对该模型系统进行全面的了解。在此基础上，可以研究经典的脂肪生成/有丝分裂转录因子簇之外的Ucp1表达控制的具体成分。因此，我们的目标是充分阐明从已经鉴定的受体到Ucp1基因启动子和增强子的信号转导的所有环节。一个重要的方面是前脂肪细胞在响应Fgf8b时大量产生的乳酸的作用，同时它会放大Fgf8b对Ucp1启动子的作用。对fgf8b募集细胞的代谢表型和形态的深入研究将辅以正在进行的转录组分析，以充分表征这种独特的表达ucp1的细胞类型。综上所述，我们建议深入了解在Fgf8b治疗下驱动表达Ucp1的前白色和棕色前脂肪细胞的细胞特性。由此产生的高度不寻常的细胞将成为理解典型的脂肪生成/有丝分裂转录因子网络之外的Ucp1基因特异性转录调控的关键，目前人们认为该网络主导着棕色脂肪细胞的整个转录特征。