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

棕色脂肪组织（BAT）是哺乳动物的一种非颤抖性产热器官。在棕色脂肪细胞线粒体中，解偶联蛋白1（Ucp 1）允许质子从膜间隙绕过ATP合酶重新进入基质，从而将ATP产生的氧消耗解偶联。通过这种机制，以质子动力形式储存的能量以热量的形式释放出来。棕色脂肪细胞并不局限于均匀的、经典的BAT贮库，而是经常发现散布在白色脂肪组织贮库中。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8 b在白色脂肪组织中招募表达Ucp 1的细胞的能力。一个主要的结果是前脂肪细胞，而不是成熟的脂肪细胞，作为检测Ucp 1转录本和蛋白质的来源的鉴定。据我们所知，这是第一次发表的观察Ucp 1表达前的前脂肪细胞/脂肪细胞谱系的终末分化，并构成了一个独特的机会，以确定和研究高度Ucp 1特异性转录调节，不是一般的棕色脂肪形成转录machinery.We的一部分，在这里建议获得一个全面的了解这个模型系统的监管，转录和代谢水平。在此基础上，它可以被用来研究特定组件的Ucp 1表达控制以外的经典脂肪/有丝分裂簇的转录因子。因此，我们的目标是充分阐明信号转导的所有环节，从已经确定的受体的Ucp 1基因启动子和增强子。一个重要的方面将是乳酸的作用，这是大量产生的前脂肪细胞在响应Fgf 8b，并在同一时间放大Fgf 8b的行动对Ucp 1启动子。Fgf 8b募集细胞的代谢表型和形态的彻底调查将补充正在进行的转录组分析，以充分表征这种独特的Ucp 1表达细胞type.In总结，我们建议获得深入了解前白色和棕色前脂肪细胞驱动表达Ucp 1响应Fgf 8b治疗的细胞身份。由此产生的，非常不寻常的细胞将作为一个关键，以了解特定的转录调控Ucp 1基因以外的典型的成脂/促有丝分裂转录因子网络目前被认为是占主导地位的棕色脂肪细胞的整个转录签名。

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.