Mosaic Mutant Analysis Identifies PDGFRα/PDGFRβ as Negative Regulators of Adipogenesis

Adipocyte progenitors (APs) express platelet-derived growth factor receptors (PDGFRs), PDGFRα and PDGFRβ. Elevated PDGFRα signaling inhibits adipogenesis and promotes fibrosis; however, the function of PDGFRs in APs remains unclear. We combined lineage tracing and functional analyses in a sequential dual-recombinase approach that creates mosaic Pdgfr mutant cells by Cre/lox recombination with a linked Flp/frt reporter to track individual cell fates. Using mosaic lineage labeling, we show that adipocytes are derived from the Pdgfra lineage during postnatal growth and adulthood. In contrast, adipocytes are only derived from the mosaic Pdgfrb lineage during postnatal growth. Functionally, postnatal mosaic deletion of PDGFRα enhances adipogenesis and adult deletion enhances β3-adrenergic-receptor-induced beige adipocyte formation. Mosaic deletion of PDGFRβ also enhances white, brown, and beige adipogenesis. These data show that both PDGFRs are cell-autonomous inhibitors of adipocyte differentiation and implicate downregulation of PDGF signaling as a critical event in the transition from AP to adipocyte. [Display omitted] •Three new Pdgfra/Pdgfrb knockin mice for mosaic mutant analysis were made•Pdgfra and Pdgfrb lineages make distinct contributions to adipocyte differentiation•Differentiation is transiently blocked by constitutive PDGFRα signaling•Mosaic Pdgfra or Pdgfrb knockout enhances white/beige/brown adipogenesis Platelet-derived growth factor receptors are markers for adult mesenchymal progenitor cells. Olson et al. analyze mice with induced functional genetic mosaicism for Pdgfra or Pdgfrb and demonstrate that both receptors cell autonomously inhibit adipocyte differentiation, which implicates downregulation of PDGF signaling as a critical event in adipogenesis.