Natural ligands of PPARγ:

The peroxisome proliferator-activated receptor (PPAR) family was discovered from an orphan nuclear receptor approach, and thereafter, three subtypes were identified, namely PPARα, PPARβ or PPARδ and PPARγ. The two former seem to regulate lipid homeostasis, whereas the latter is involved, among others, in glucose homeostasis and adipocyte differentiation. PPARs were pharmacologically characterised first using peroxisome proliferators such as clofibrates, which demonstrate moderate affinity (efficiency at micromolar concentrations) and low PPARα/δ versus PPARγ specificity. Hence, several laboratories have started the search for potent and subtype-specific natural PPAR activators. In this respect, prostaglandin (PG)-related compounds were identified as good PPARγ agonists with varying specificity, the most notable PPARγ ligand being 15-deoxy-Δ12–14-PGJ2 (15d-PGJ2). Recently, an oxidized phosphatidylcholine was identified as a potent alternative (patho)physiological natural ligand of PPARγ. In the present review, we discuss the different PPARγ-dependent and -independent biological effects of the PG PPARγ ligands and the concern about their low potency in molecular models as compared with thiazolidinediones (TZDs), a family of potent (nanomolar) synthetic PPARγ ligands. Finally, the oxidized lipids are presented as a novel and interesting alternative for discovering potent PPARγ activators in order to understand more in details the implications of PPARγ in various pathophysiological conditions.