439 Mechanism for loss of intradermal fat accompanying skin fibrosis

Abstract

Fibrotic diseases contribute to approximately 45% of deaths in Europe and North America, and are characterized by an accumulation of extracellular matrix and loss of lipid-filled cells. Dermal fibrosis is a debilitating disease which serves as a model for studying universal trends in fibrosis such as lipid depletion. Intradermal adipocytes comprising the dermal white adipose tissue (DWAT) have diverse functions impacted by their lipid content. The mechanisms governing DWAT lipid depletion are not known nor are the effects of lipid depletion in causing fibrosis. Wnt signaling is dysregulated among fibrotic tissues and sustained Wnt signaling in mouse dermis is sufficient to cause dermal fibrosis including DWAT lipid depletion. Here we tested the following hypothesis: Wnt signaling and Wnt-responsive factors cause DWAT lipid depletion and subsequent dermal thickening. We developed a genetic mouse model of Wnt activation in the dermis resulting in inducible and reversible dermal thickening preceded by DWAT lipid depletion, enabling us to identify mediators of Wnt-induced lipid depletion. Wnt activation in intradermal adipocytes in vitro leads to lipid loss by induction of lipolysis, as indicated by a three-fold increase in free glycerol, suggesting Wnt signaling causes cell autonomous lipolytic effects. Additionally, conditioned media from Wnt-activated fibroblasts stimulate lipid loss in intradermal adipocytes in vitro, implicating intercellular communication in fibrotic adipocyte lipid loss. Finally, transient inhibition of a candidate Wnt-responsive factor, CD26/DPPIV, in genetic and chemical models of fibrosis leads to preservation or faster recovery of lipid in DWAT and reduced dermal thickness in vivo, demonstrating that Wnt-DPPIV modulates lipid homeostasis in adipocytes impacting neighboring dermal fibroblasts. Thus, we propose to treat dermal fibrosis in a pre-clinical model with FDA-approved drugs by targeting a new cellular player in fibrosis.