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

Abstract

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-arachidonoyl-dopamine, HU210, WIN55212-2 and CP55940. In contrast, little research has been carried out on the effects of cannabinoids at PPAR delta. 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.

Figure 1

Chemical structure of known PPARα and PPARγ ligands, and of cannabinoids known to activate PPARs, including anandamide, which appears to be a dual agonist of both PPARα and PPARγ.

Figure 2

Mechanisms of time-dependent vasorelaxation to THC in isolated blood vessels. THC activates PPARγ within endothelial cells, leading to the transcription and translation of target proteins. One protein identified is superoxide dismutase (SOD), which can prevent NO being scavenged by endogenous superoxide anion, and also catalyses the conversion of superoxide to H₂O₂, both of which cause vasorelaxation of underlying smooth muscle (O'Sullivan et al., 2005). Other PPARγ ligands (ciglitazone or 15d-PGJ₂) also enhance NO bioavailability through induction of SOD (Hwang et al., 2005). Pre-incubation with THC also promotes agonist-stimulated vasorelaxation (to acetylcholine) by similar mechanisms (O'Sullivan et al., 2006a, 2006b). 15d-PGJ₂, 15-deoxy-Δ-12,14-prostaglandin J₂; H₂O₂, hydrogen peroxide; NO, nitric oxide; PPARs, peroxisome proliferator-activated receptors; THC, Δ⁹-tetrahydrocannabinol.

Figure 3

Potential mechanisms of cannabinoid/PPAR interactions. (1) Some studies have shown that cannabinoids and endocannabinoids directly bind to PPARs to bring about changes in target gene expression. (2) Some studies have implicated that it is the conversion of cannabinoids into metabolites, which are active at PPARs. (3) A third possibility is that cannabinoids, acting at cell surface receptors, may initiate intracellular signalling cascades that lead to the activation of PPARs. Potentially, all three pathways contribute to the effects of cannabinoid at PPARs, and the relative contributions of each pathway may be different between cells and tissues depending on the expression of various receptors and enzymes within that cell. PPARs, peroxisome proliferator-activated receptors.