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

Cannabinoids act at two classical cannabinoid receptors (CB1 and CB2), 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 alpha, beta (delta) and gamma), which regulate cell differentiation and lipid metabolism. Much evidence now suggests that endocannabinoids are natural activators of PPAR alpha. Oleoylethanolamide regulates feeding and body weight, stimulates fat utilization and has neuroprotective effects mediated through activation of PPAR alpha. Similarly, palmitoylethanolamide regulates feeding and lipid metabolism and has anti-inflammatory properties mediated by PPAR alpha. Other endocannabinoids that activate PPAR alpha include anandamide, virodhamine and noladin. Some (but not all) endocannabinoids also activate PPAR gamma; anandamide and 2-arachidonoylglycerol have anti-inflammatory properties mediated by PPAR gamma. Similarly, ajulemic acid, a structural analogue of a metabolite of Delta(9)-tetrahydrocannabinol (THC), causes anti-inflammatory effects in vivo through PPAR gamma. THC also activates PPAR gamma, leading to a time-dependent vasorelaxation in isolated arteries. Other cannabinoids which activate PPAR gamma include N-arachidonoyldopamine, HU210, WIN55212-2 and CP55940. In contrast, little research has been carried out on the effects of cannabinoids at PPAR gamma. 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 alpha and PPAR gamma agonists? This review will summarize the published literature implicating cannabinoid-mediated PPAR effects and discuss the implications thereof.