Peroxisome proliferator-activated receptor gamma activation reverses adipose tissue regulatory T cell dysfunction

Abstract Adipose tissue (AT) regulatory T Cells (Tregs) play an essential role in regulating inflammatory and metabolic responses. Obesity is associated with a decrease in AT Tregs and a corresponding increase in tissue inflammation and systemic insulin resistance in both humans and mice. In human samples, we have found Tregs isolated from visceral AT (VAT) display a dysfunctional phenotype characterized by decreased viability, decreased effector function, and increased expression of inhibitory co-receptors (PD-1 and OX40). VAT Tregs cultured with peripheral blood mononuclear cells (PBMCs) display reduced ability to suppress proliferation, while peripheral blood Tregs suppress proliferation normally. As peroxisome proliferator-activated receptor (PPAR)-gamma has been shown to be a regulator of AT Tregs, we hypothesize that the Treg dysfunction can be reversed by addition of the PPAR-gamma agonist Pioglitazone. We isolated Tregs from VAT and peripheral blood and added cells to CFSE-labelled PBMCs in the presence and absence of Pioglitazone. After 4 days culture, Pioglitazone was found to significantly improve the ability of VAT Tregs to suppress proliferation. This effect was specific to AT Treg populations as Pioglitazone alone did not affect PBMC proliferation. These data suggest that Treg dysfunction contributes to AT inflammation and activation of PPAR-gamma promotes VAT-specific Treg activity providing therapeutic implications for PPAR-gamma agonists. (Partially supported by the OSU Cancer Center Support Grant P30CA016058).