Contribution of Adipocytes and Adipose Secreted Factors to Fibrosis in Systemic Sclerosis

Systemic sclerosis (SSc, scleroderma) is a complex and devastating disease which is characterized by progressive fibrosis of the skin and internal organs. SSc has the highest case-fatality rate of any connective tissue disease with a 55% 10-year survival, and affects an estimated 100,000 Americans. Despite recent advances in disease pathogenesis, there are no currently approved or effective therapies to slow progressive organ fibrosis in SSc. Most SSc research to date has focused on the fibroblast as the key effector cell in fibrosis and disease progression. However, recent work from our lab provides evidence that adipocytes play a significant role in fibrosis. Patients with SSc have a marked reduction in intradermal adipose tissue, and we made the observation that this reduction in adipose correlates inversely with increased skin fibrosis. This association of reduced intradermal adipose and skin fibrosis is seen in over ten animal models of skin fibrosis. Moreover, we have recently shown that in bleomycin-induced skin fibrosis, loss of intradermal adipose precedes dermal fibrogenesis. Given these observations, there is a strong possibility that loss of intradermal adipose is a pathogenic event in fibrosis and that intradermal adipose tissue is essential in skin homeostasis and regulation of dermal fibrogenesis. However, what is not known is how intradermal adipose tissue regulates connective tissue and, more importantly, how adipose tissue mediates skin fibrosis in SSc. I hypothesize that intradermal adipocytes secrete anti-fibrotic factors to maintain skin homeostasis and resist fibrosis because of adipocytes’ multiple metabolic roles and increasing evidence that intradermal adipose tissue plays an active role in regulation of multiple aspects of skin biology through paracrine effects. To define and better characterize the protective role of adipocytes in skin fibrosis and elucidate the mechanism, I will utilize genetic mouse models, ex vivo systems, and transcriptomic approaches.