Tcf21 and visceral adipose tissue development and expansion - 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
α (PDGFRα), 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 PDGFRα.
The central hypothesis of the proposed studies is that Tcf21 promotes the fate specification and
hyperplasia of adipogenic progenitor cells in VAT through targeting PDGFRα. 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
PDGFRα in the Tcf21 regulation of VAT development and expansion.
