A remaining question is whether the effects on alcohol consumption are mediated by PPAR-dependent or -independent mechanisms. A comparison of wild-type endothelial cells and endothelial cells lacking PPARα showed that only 26% of differentially expressed genes were PPARα-dependent after 18 hours of fenofibrate treatment 4. PPAR-independent mechanisms have also been implicated in other brain disorders. For example, inhibition of Cdk5 via a PPARγ-independent pathway decreased tau phosphorylation, a mechanism implicated in the positive effects of PPARγ agonists in Alzheimer’s disease 12. Evidence also points to a non-transcriptional (phosphorylation-mediated) interaction between PPARα and the nAChR that at least partly mediates PPARα agonist effects on nicotine dependence 33. Experiments using PPAR subunit knock-out strategies are needed to determine if the effects of feno and tesa on alcohol-consumption are PPAR-dependent or -independent.
