White adipose tissue (WAT) is divided into two categories, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), based on their anatomical locations. A specific positive correlation has been suggested between pathologic VAT expansion and insulin resistance, which makes VAT a potential target for treating metabolic diseases such as type 2 diabetes (T2D). Because of the beneficial effect of SAT on metabolism, research specifically focusing on the VAT-specific regulation of adipogenesis without affecting SAT is needed to further elucidate the specific relationship between VAT and insulin resistance and design appropriate VAT-targeted therapeutic strategies. Tcf21 is a recently identified basic helix-loop-helix transcription factor exclusively expressed in VAT. Its expression in SAT and brown adipose tissue (BAT) is negligible. It was reported that Tcf21 is critical for the cell fate specification and expansion of mesenchymal cells residing in several visceral organs during development. Although the mechanism is still not clear, it is suggested that Tcf21 promotes the epithelial-mesenchymal transition (EMT) and proliferation of progenitor cells, the two processes also required for VAT development and expansion. Using motif-finding algorithms, we identified multiple putative Tcf21 binding sites in the promoter of the gene encoding platelet-derived growth factor receptor ? (PDGFR?), a gene widely expressed in progenitor cells that can give rise to adipocytes. In this application, experiments are proposed to investigate the functional role of Tcf21 in VAT development and expansion, and study if the functional role of Tcf21 in VAT requires PDGFR?. The central hypothesis of the proposed studies is that Tcf21 promotes the fate specification and hyperplasia of adipogenic progenitor cells in VAT through targeting PDGFR?. The objective of this proposal is to elucidate the mechanisms by which Tcf21 fulfills its functions at the molecular, cellular and organismic levels, and to explore its therapeutic potential.
In Aim #1, novel mouse lines with Tcf21 lineage-specific tamoxifen-inducible Tcf21 knockout or overexpression, and Tcf21 lineage tracing will be used to rigorously examine the functional role of Tcf21 in the development and expansion of VAT. The feasibility of treating metabolic disorder through targeting Tcf21 will also be investigated.
In Aim #2, Pdgfra-LoxP mice will be crossed with mouse lines described in Aim #1 to study the necessity of PDGFR? in the Tcf21 regulation of VAT development and expansion.
Pathological expansion of visceral adipose tissue is associated with the development of insulin resistance. The proposed research will explore the depot-specific regulation of visceral adipose tissue development and expansion by Tcf21, which will reveal novel therapeutic targets for treating insulin resistance. If the application is funded, this public health relevance statement will be combined with the project summary (above) and will become public information.
