Summary Chronic fibrosis is the pathological hallmark in a variety of disorders in many organs including the skin in patients with systemic and limited sclerosis, aggressive fibromatoses, keloid, hypertrophic scarring, and atopic dermatitis. Our laboratories recently uncovered an unexpected and intriguing role for mature adipocytes during skin fibrosis: repression of ECM production. In particular, we identified that mature adipocytes undergo lipolysis to release fatty acids in a Wnt-dependent mechanism and that adipocyte lipolysis is fibroprotective. Our findings are important for several reasons. First, adipocytes have been shown to improve scarring yet how mature adipocytes function in this process is unclear. Second, adipose tissue loss is a major clinical issue in the skin and an early event in the development of skin fibrosis. Furthermore, adipocytes and their derivatives (fatty acids and/or cytokines) are a tractable cell type to create a personalized therapy to promote healing in patients with fibrosis. Through two focused and complementary Specific Aims, the work proposed in this application will take advantage of multiple genetic mouse models that allow specific abrogation of adipocyte lipolysis and fibrosis development, lipidomics, and fibroblast culture assays to define the function of adipocyte lipolysis during skin fibrosis. Our goals are to test whether: 1. adipocyte-derived fatty acids abrogate ECM production during fibrosis development; and 2. Wnts stimulate lipolysis of dermal adipocytes. Towards these goals, in Aim1, we will define the cellular and molecular changes by which lipolysis alters mouse skin and if dermal adipocyte lipids can abrogate the fibrotic response in mouse and human fibrotic fibroblasts or other cell types. In Aim2, we will test the role of Wnts and its new candidate effector, Dipeptidyl dipeptidase 4 in stimulating lipolysis in chemical and genetic models in vivo and in vitro. Results from these studies will provide a role for dermal adipocyte derived fatty acids and Wnt signaling targets as new therapeutic targets in chronic skin fibrosis and associated lipodystrophy. Impact: We propose to study the function of adipocyte lipids and Wnt signaling induced lipolysis in context of dermal fibrosis. These results will reveal novel cell types and molecular pathways involved in lipid depletion that can be a key regulator of fibrosis development and reversal. Results from these experiments will elucidate the contribution of intradermal adipocytes and lipolysis as new participants and will change the field by opening new lines of inquiry and therapeutic targets.