Gene Doping with Peroxisome-Proliferator-Activated Receptor Beta/Delta Agonists Alters Immunity but Exercise Training Mitigates the Detection of Effects in Blood Samples

Abstract

Synthetic ligands of peroxisome-proliferator-activated receptor beta/delta (PPARβ/δ) are being used as performance-enhancing drugs by athletes. Since we previously showed that PPARβ/δ activation affects T cell biology, we wanted to investigate whether a specific blood T cell signature could be employed as a method to detect the use of PPARβ/δ agonists. We analyzed in primary human T cells the in vitro effect of PPARβ/δ activation on fatty acid oxidation (FAO) and on their differentiation into regulatory T cells (Tregs). Furthermore, we conducted studies in mice assigned to groups according to an 8-week exercise training program and/or a 6-week treatment with 3 mg/kg/day of GW0742, a PPARβ/δ agonist, in order to (1) determine the immune impact of the treatment on secondary lymphoid organs and to (2) validate a blood signature. Our results show that PPARβ/δ activation increases FAO potential in human and mouse T cells and mouse secondary lymphoid organs. This was accompanied by increased Treg polarization of human primary T cells. Moreover, Treg prevalence in mouse lymph nodes was increased when PPARβ/δ activation was combined with exercise training. Lastly, PPARβ/δ activation increased FAO potential in mouse blood T cells. Unfortunately, this signature was masked by training in mice. In conclusion, beyond the fact that it is unlikely that this signature could be used as a doping-control strategy, our results suggest that the use of PPARβ/δ agonists could have potential detrimental immune effects that may not be detectable in blood samples.

PPARs as Key Mediators in the Regulation of Metabolism and Inflammation

“…Interestingly, synthetic ligands of PPARβ/δ can enhance performance in athletes and are included as S4.5 Metabolic Modulators in the World Anti-Doping Agency's (WADA) Prohibited List. Sibille et al [19] investigated whether a specific signature in blood T cells could identify the ingestion of the prohibited PPARβ/δ agonist GW0742. PPARβ/δ activation by GW0742 has been shown to stimulate fatty acid oxidation (FAO) in mouse and human T cells, with increased Treg polarization of human primary T cells.…”