PPARγ promotes age-related thymic involution (64.12)

Abstract

Abstract Aging of the thymus precedes aging of other organs in healthy adults. The decline in naïve T cell production from thymus is related with ectopic adipocyte development within the lympho-stromal thymic zones. The regulators responsible for age-related increase in thymic adiposity and reduced thymopoiesis are poorly understood. Our prior data suggests that age-related elevation of PPARγ expression in aP2 expressing thymic stromal cells in correlated with thymic adiposity. To directly investigate whether PPARγ activation induces thymic involution, we created transgenic mice with constitutive active PPARγ (CA-PPARγ) fusion protein driven by an aP2 promoter. The CA-PPARγ transgene was expressed in thymus and CA-PPARγ fusion protein mimicked the liganded PPARγ receptor. The CA-PPARγ mice had increased thymic adipogenesis, thymic involution, reduced thymopoeisis and restricted T cell receptor (TCR) repertoire diversity. In addition, the ligand activation of PPARγ by insulin sensitizing class of thiazolidinediones drug, rosiglitazone accelerated the PPARγ driven thymic adipogenic cascade and promoted thymic involution andreduced naïve T cells. Our data suggest that activation of PPARγ induces thymic adiposity and accelerates age-related thymic involution.