Thiazolidinedione treatment and constitutive-PPARγ activation induces ectopic adipogenesis and promotes age-related thymic involution

P>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 (PPAR gamma) 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 PPAR gamma 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 PPAR gamma leads to reduction in thymopoiesis. Treatment of aged mice with antihyperglycemic PPAR gamma-ligand class of thiazolidinedione drug, rosiglitazone caused robust thymic expression of classical pro-adipogenic transcripts. Rosiglitazone reduced thymic cellularity, lowered the naive T cell number and T cell receptor excision circles (TRECs) indicative of compromised thymopoiesis. To directly investigate whether PPAR gamma activation induces thymic involution, we created transgenic mice with constitutive-active PPAR gamma (CA-PPARg) fusion protein in cells of adipogenic lineage. Importantly, CA-PPAR gamma transgene was expressed in thymus and in fibroblast-specific protein-1/S100A4 (FSP1+) cells, a marker of secondary mesenchymal cells. The CAPPAR gamma fusion protein mimicked the liganded PPAR gamma receptor and the transgenic mice displayed increased ectopic thymic adipogenesis and reduced thymopoiesis. Furthermore, the reduction in thymopoiesis in CA-PPAR gamma mice was associated with higher bone marrow adiposity and lower hematopoietic stem cell progenitor pool. Consistent with lower thymic output, CAPPAR gamma transgenic mice had restricted T cell receptor repertoire diversity. Collectively, our data suggest that activation of PPAR gamma accelerates thymic aging and thymus-specific PPAR gamma antagonist may forestall age-related decline in T cell diversity.