Cannabinoids go nuclear: evidence for activation of peroxisome proliferator‐activated receptors

Cannabinoids act at two classical cannabinoid receptors (CB 1 and CB 2 ), a 7TM orphan receptor and the transmitter‐gated channel transient receptor potential vanilloid type‐1 receptor. Recent evidence also points to cannabinoids acting at members of the nuclear receptor family, peroxisome proliferator‐activated receptors (PPARs, with three subtypes α , β ( δ ) and γ ), which regulate cell differentiation and lipid metabolism. Much evidence now suggests that endocannabinoids are natural activators of PPAR α . Oleoylethanolamide regulates feeding and body weight, stimulates fat utilization and has neuroprotective effects mediated through activation of PPAR α . Similarly, palmitoylethanolamide regulates feeding and lipid metabolism and has anti‐inflammatory properties mediated by PPAR α . Other endocannabinoids that activate PPAR α include anandamide, virodhamine and noladin. Some (but not all) endocannabinoids also activate PPAR γ ; anandamide and 2‐arachidonoylglycerol have anti‐inflammatory properties mediated by PPAR γ . Similarly, ajulemic acid, a structural analogue of a metabolite of Δ 9 ‐tetrahydrocannabinol (THC), causes anti‐inflammatory effects in vivo through PPAR γ . THC also activates PPAR γ , leading to a time‐dependent vasorelaxation in isolated arteries. Other cannabinoids which activate PPAR γ include N ‐arachidonoyl‐dopamine, HU210, WIN55212‐2 and CP55940. In contrast, little research has been carried out on the effects of cannabinoids at PPARδ. In this newly emerging area, a number of research questions remain unanswered; for example, why do cannabinoids activate some isoforms and not others? How much of the chronic effects of cannabinoids are through activation of nuclear receptors? And importantly, do cannabinoids confer the same neuro‐ and cardioprotective benefits as other PPAR α and PPAR γ agonists? This review will summarize the published literature implicating cannabinoid‐mediated PPAR effects and discuss the implications thereof. British Journal of Pharmacology (2007) 152 , 576–582; doi: 10.1038/sj.bjp.0707423 ; published online 20 August 2007