105 Wnt signaling stimulates ATGL-regulated lipolysis in dermal fibrosis

Fibrotic disorders, characterized by the deposition of excessive extracellular matrix in all organs and the loss of lipid-filled cells in several organs, contribute to approximately 45% of deaths in Europe and North America. Skin has a distinct dermal white adipose tissue (DWAT) compartment, making dermal fibrosis a good model for studying fibrotic fat loss. DWAT adipocytes perform various functions impacted by their lipid content. A primary process by which adipocytes homeostatically modulate their lipid content and mobilize stored lipid is adipose triglyceride lipase (ATGL)-regulated lipolysis. The mechanisms underlying fibrotic fat loss in DWAT and the impact of lipid depletion in fibrosis are unknown. Wnt signaling is dysregulated in human fibrosis and has known anti-adipogenic roles. We hypothesize that dermal Wnt signaling activation stimulates ATGL-regulated lipolysis leading to fibrotic lipid depletion. Using a genetically inducible and reversible mouse model of dermal Wnt activation, we show Wnt activation is sufficient to cause dermal fibrosis. The ATGL-regulated lipolysis axis is activated in DWAT adipocytes during the onset and progression of Wnt-induced fibrosis. Dermal Wnt activation leads to elevated phosphorylated hormone sensitive lipase and phosphorylated perilipin, lipolytic proteins downstream of ATGL, preceding fibrotic fat loss in vivo. Wnt activation also leads to a reduction in the size of perilipin-positive adipocyte lipid droplets in vivo. Thus, stimulated ATGL-regulated lipolysis occurs as an early event in dermal fibrosis. Consistently, murine primary intradermal adipocytes release more glycerol, a product of lipolysis, upon Wnt activation in vitro indicating that Wnt signaling has cell-autonomous lipolytic effects. ATGL enzymatic inhibition is sufficient to rescue Wnt-induced lipolysis. Current studies focus on the role of ATGL in Wnt-induced dermal fibrosis in vivo. Our results implicate lipolysis as a novel therapeutic target for fibrosis treatment.