184 Wnt-induced excessive lipolysis drives fat loss in skin fibrosis

Fibrotic disorders contribute to approximately 45% of deaths in Europe and North America. Fibrosis affects all soft tissues, and is characterized by the deposition of excessive extracellular matrix in all organs and the loss of lipid-filled cells in most organs. Dermal fibrosis is a good model for studying fibrosis-associated lipid depletion due to the distinct dermal white adipose tissue (DWAT) compartment in the lower dermis, which modulates angiogenesis and immune cell recruitment. The mechanisms underlying fibrosis-associated lipid depletion are unknown. Although adipocytes homeostatically activate ATGL-dependent lipolysis in order to break down stored lipids into extracellular glycerol and fatty acids, stimulated lipolysis can lead to rapid lipid depletion. Wnt signaling is dysregulated in human fibrosis, and sustained Wnt signaling is sufficient to cause dermal fibrosis including DWAT lipid depletion in mice. We hypothesized that dermal Wnt signaling activation stimulates ATGL-dependent lipolysis. We developed a genetic mouse model of dermal Wnt activation allowing for inducible and reversible dermal ECM expansion, with which we were able to quantify the dynamics of dermal lipid depletion during the onset and progression of Wnt-induced fibrosis. Dermal Wnt activation led to an increase in the activated lipolytic enzyme downstream of ATGL, phosphorylated HSL, preceding DWAT loss in vivo, showing stimulated lipolysis as an early event in dermal fibrosis. Consistently, Wnt-activation in murine intradermal adipocytes in vitro released three times as much glycerol as untreated adipocytes, indicating that Wnt signaling has cell-autonomous lipolytic effects. Subsequently, we found that enzymatic inhibition of a key lipolytic enzyme, ATGL, is sufficient to rescue Wnt-induced lipolysis. Current studies are focused on the role of ATGL in Wnt-induced dermal fibrosis in vivo. Our results implicate lipolysis as a potential therapeutic target for fibrosis treatment.