Cell Stem Cell
Volume 26, Issue 5, 7 May 2020, Pages 707-721.e5
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Article
Mosaic Mutant Analysis Identifies PDGFRα/PDGFRβ as Negative Regulators of Adipogenesis

https://doi.org/10.1016/j.stem.2020.03.004Get rights and content
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Highlights

  • 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

Summary

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.

Keywords

adipocyte progenitor
adventitia
fibroblast
mural cell
obesity
vascular wall

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6

These authors contributed equally

7

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