Parallel Lineage-Tracing Studies Establish Fibroblasts as the Prevailing In Vivo Adipocyte Progenitor

Despite decades of studies suggesting that the in vivo adipocyte progenitor resides within the vascular niche, the exact nature of this progenitor remains controversial because distinct studies have attributed adipogenic properties to multiple vascular cell types. Using Cre recombinases labeling distinct vascular lineages, we conduct parallel lineage tracing experiments to assess their degree of contribution to de novo adipogenesis. Although we detect occasional adipocytes that were lineage traced by endothelial or mural recombinases, these are rare events. On the other hand, platelet-derived growth factor receptor alpha (PDGFRα)-expressing adventitial or capsular fibroblasts make a significant contribution to adipocytes in all depots and experimental settings tested. Our data also suggest that fibroblasts transition to an intermediate beige adipocyte phenotype prior to differentiating to a mature white adipocyte. These observations, together with histological analyses revealing that adipose tissue fibroblasts express the mural cell marker PDGFRβ, harmonize a highly controversial field with implications for multiple human diseases, including the pandemic of obesity. [Display omitted] •In adipose tissue (AT), PDGFRβ expression is not specific to mural cells•Mural and endothelial cells have no significant adipogenic potential•Fibroblasts have significant adipogenic potential in both white and brown AT•Fibroblasts significantly contribute to the beiging of white AT Cattaneo et al. used genetic fate mapping in murine models to test the adipogenic potential of distinct cell types of the vascular wall. These parallel lineage-tracing experiments reveal that fibroblasts are the sole vascular cell type with significant adipocyte progenitor activity, giving rise to brown, beige, and white adipocytes.