Ma_2025_Faseb.j_39_e70830

Accumulation of extracellular matrix (ECM) and dermal adipocyte lipodystrophy occurs during skin fibrosis, which compromises the skin's flexibility and function. Sustained Wnt activation in dermal progenitor cells leads to fibrotic ECM thickening in the dermis and lipodystrophy of dermal white adipose tissue (DWAT). Mouse genetic models with lineage tracing demonstrate that Wnt activation in mature dermal adipocytes is sufficient to induce adipocyte lipodystrophy and fibrotic ECM remodeling in the skin. Upon withdrawal of adipocyte-restricted Wnt activation, lipodystrophy and fibrosis are reversed. Mechanistically, Wnt activation stimulates the Adipose Triglyceride Lipase (ATGL)-mediated lipolysis pathway, and lipolysis is an early event in the skin of Systemic Sclerosis patients. Atgl in dermal adipocytes is functionally required for Wnt-induced lipodystrophy in the DWAT and fibrotic remodeling. Collectively, this study demonstrates that Wnt activation in dermal adipocytes promotes lipolysis, suggesting a therapeutic avenue for the treatment of lipodystrophy and skin fibrosis.