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

• Applicant: Privatdozent Dr. Tobias Fromme
• Subject Area: Nutritional Sciences ; Animal Physiology and Biochemistry
• Term: from 2016 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 321208980

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. 

• DFG Programme: Research Grants