Peroxisome proliferator-activated receptor gamma (PPARgamma): Is the genomic activity the only answer?

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear hormone receptor superfamily of transcription factors, widely expressed in the organism, including adipose, vascular and immune cells. Besides the well-known role in lipid/glycidic homeostasis, PPARgamma has also recently emerged as a key regulator of inflammatory and immune responses. Besides the natural ligands, more potent synthetic agonists of PPARgamma have been developed, including thiazolidinediones (TZDs), currently used in type 2 diabetes treatment, which also exert anti-inflammatory and anti-neoplastic effects. PPARgamma mechanism of action has focused considerable attention over the years. This receptor was initially shown to act on gene expression through a direct transcription and an indirect transrepression activity, mainly associated with metabolic and anti-inflammatory effects. Different post-translational modifications of the receptor can modulate PPARgamma activity. More recently, rapid nongenomic activity of TZDs affecting post-translation modifications of extranuclear proteins involved in cell signaling, has been reported. In particular, PPARgamma can physically interact with protein kinases resulting in a compartment specific recruitment and activity modulation of these enzymes. Among them, ERK can be positively/negatively regulated by PPARgamma ligands, as in endothelial cells, where TZDs exert anti-inflammatory effects through a novel mechanism involving a rapid inhibition of ERK1/2 phosphorylation/activation. Finally, some of the TZD anti-tumor effects seem to be PPARgamma-independent, raising the possibility that alternative receptors can act through extranuclear nongenomic pathways. In conclusion, different mechanisms of action of PPARgamma seem to coexist in an interacting functional network in the cell, concurring in mediating both pharmacological and natural ligand effects.