Thiazolidinedione treatment and constitutive-PPARgamma activation induces ectopic adipogenesis and promotes...

Age-related thymic involution is characterized by reduction in T cell production together with ectopic adipocyte development within the hematopoietic and thymic niches. Peroxisome proliferator-activated receptor gamma (PPARgamma) is required for adipocyte development, glucose homeostasis and is a target for several insulin-sensitizing drugs. Our prior studies showed that age-related elevation of PPARgamma expression in thymic stromal cells is associated with thymic involution. Here, using clinically relevant pharmacological and genetic manipulations in mouse models, we provide evidence that activation of PPARgamma leads to reduction in thymopoiesis. Treatment of aged mice with antihyperglycemic PPARgamma-ligand class of thiazolidinedione drug, rosiglitazone caused robust thymic expression of classical pro-adipogenic transcripts. Rosiglitazone reduced thymic cellularity, lowered the naïve T cell number and T cell receptor excision circles (TRECs) indicative of compromised thymopoiesis. To directly investigate whether PPARgamma activation induces thymic involution, we created transgenic mice with constitutive-active PPARgamma (CA-PPARg) fusion protein in cells of adipogenic lineage. Importantly, CA-PPARgamma transgene was expressed in thymus and in fibroblast-specific protein-1/S100A4 (FSP1(+)) cells, a marker of secondary mesenchymal cells. The CAPPARgamma fusion protein mimicked the liganded PPARgamma receptor and the transgenic mice displayed increased ectopic thymic adipogenesis and reduced thymopoiesis. Furthermore, the reduction in thymopoiesis in CA-PPARgamma mice was associated with higher bone marrow adiposity and lower hematopoietic stem cell progenitor pool. Consistent with lower thymic output, CAPPARgamma transgenic mice had restricted T cell receptor repertoire diversity. Collectively, our data suggest that activation of PPARgamma accelerates thymic aging and thymus-specific PPARgamma antagonist may forestall age-related decline in T cell diversity.