A PDGFRα-Mediated Switch toward CD9high Adipocyte Progenitors Controls Obesity-Induced Adipose Tissue Fibrosis

Obesity-induced white adipose tissue (WAT) fibrosis is believed to accelerate WAT dysfunction. However, the cellular origin of WAT fibrosis remains unclear. Here, we show that adipocyte platelet-derived growth factor receptor-alpha-positive (PDGFR alpha(+)) progenitors adopt a fibrogenic phenotype in obese mice prone to visceral WAT fibrosis. More specifically, a subset of PDGFR alpha(+) cells with high CD9 expression (CD9(high)) originates pro-fibrotic cells whereas their CD9(low) counterparts, committed to adipogenesis, are almost completely lost in the fibrotic WAT. PDGFRa pathway activation promotes a phenotypic shift toward PDGFR alpha(+) CD9(high) fibrogenic cells, driving pathological remodeling and altering WAT function in obesity. These findings translated to human obesity as the frequency of CD9(high) progenitors in omental WAT (oWAT) correlates with oWAT fibrosis level, insulin-resistance severity, and type 2 diabetes. Collectively, our data demonstrate that in addition to representing a WAT adipogenic niche, different PDGFR alpha(+) cell subsets modulate obesity-induced WAT fibrogenesis and are associated with loss of metabolic fitness.