5-OR: Tcf21 Functions as a Rate-Limiting Factor during Visceral Adipose Tissue Development

Using an inducible lineage-tracing mouse line, we identified that Tcf21, a bHLH transcription factor gene, is expressed in visceral adipose tissue (VAT) but not in subcutaneous adipose tissue. In VAT, Tcf21 is expressed in mesenchymal progenitor cells but not in adipocytes. Tcf21 lineage progenitor cells actively proliferate followed by differentiation into adipocytes during neonatal development but have limited adipogenic capacity in adult mice even when fed with a high-fat diet (HFD) . Bulk RNAseq and ATACseq analyses of Tcf21 lineage progenitor cells isolated from mice of different ages or adiposities revealed the dynamic gene expression and chromatin accessibility in Tcf21 lineage progenitor cells. In particular, higher expression of pro-mitotic genes was observed in neonatal mice followed by an elevation of pro-adipogenic gene expression. Increased expression of inflammatory genes and fibrotic genes was observed in Tcf21 lineage progenitor cells from obese mice. Using transcriptomic and motif enrichment data, we constructed a gene regulatory network mediating the gene expression changes in Tcf21 lineage progenitor cells. Single-cell RNAseq and immunostaining identified multiple subpopulations of Tcf21 lineage cells including 2 major subpopulations including a mesothelial subpopulation and an interstitial subpopulation. Using an inducible cell-type-specific Tcf21 KO mouse line, we identified that neonatal deletion of Tcf21 in Tcf21 lineage progenitor cells led to their increased adipogenic differentiation during postnatal development and improved metabolism after HFD treatment. In vitro loss-of-function and gain-of-function studies showed that Tcf21 inhibits the adipogenic differentiation of VAT progenitor cells. Mechanistic studies identified that Tcf21 inhibits adipogenesis and developmental progress of VAT progenitor cells through promoting the expression of Dlk1, a negative regulator of adipogenesis, mainly in the interstitial subpopulation.