Cannabinoid activation of peroxisome proliferator‐activated receptors: an update and review of the physiological relevance

Abstract

Since 2002, evidence has been building that cannabinoids, including endocannabinoids and endocannabinoid-like compounds, phytocannabinoids and synthetic cannabinoid ligands, bind to and activate the different isoforms of the nuclear receptors, peroxisome proliferator-activated receptors (PPARs; α, β, and γ ). This has been shown through the use of reporter gene assays, binding studies, the use of antagonists and knockout animals. Increasing use of tools to assess a potential role for PPAR activation in underpinning the physiological effects of cannabinoids means that a picture is emerging of the relevance of PPAR activation by cannabinoids. There is now evidence that activation of PPARα and γ mediate some of the anti-inflammatory, analgesic, neuroprotective, and cardiovascular effects of cannabinoids, sometimes in combination with activation of the more traditional target sites of action such as CB 1 , CB 2 , and TRPV1. There is also a role for PPARα activation by cannabinoids in some of their central effects including memory acquisition, reward processing, food intake and body weight regulation. Activation of PPARγ plays a role in the apoptotic effects of cannabinoids. However, much further work is required to fully establish the profile of cannabinoid compounds at all isoforms of the PPAR family and the relevance of this in normal physiology and pathological situations.

An update on PPAR activation by cannabinoids

“…The aims of this review were to update the evidence that cannabinoids have “gone nuclear” and to establish whether activation by cannabinoids of the PPARs, a major class of nuclear hormone receptors, plays a role in their physiological effects (O'Sullivan, ; O'Sullivan, ). Although our knowledge in this area has significantly increased, there are still many cannabinoids whose activity at PPARs remains unknown.…”

“…Since 2002, evidence has accumulated that endocannabinoids, endocannabinoid‐like compounds, phytocannabinoids and synthetic cannabinoid ligands bind to and activate PPARs (O'Sullivan, ; O'Sullivan, ). This link has been identified through reporter gene assays, binding studies, the use of selective antagonists, knockout animals and siRNA knockdown studies, and these data are summarized in Tables and .…”

Phytocannabinoids—A Green Approach toward Non-Alcoholic Fatty Liver Disease Treatment

“…In recent years, it has been suggested that non-cannabinoid receptors such as peroxisome proliferator-activated receptors (PPARs) are also part of the endocannabinoid system [68]. These nuclear factors have three isotypes (PPARα, PPARß/δ, PPARγ), and they are characterized by different tissue distribution patterns and ligand specificities, which highlight their distinct functions [69].…”

“…Since 2002, evidence has existed that endocannabinoids, endocannabinoid-like compounds, phytocannabinoids, and synthetic cannabinoid ligands bind to and activate PPARs [68]. The mechanisms of PPAR activation by individual phytocannabinoids have been summarized by O'Sullivan et al, who revealed that THC and CBD activate PPAR γ and do not activate PPARα [69].…”

Efficacy of Phytocannabinoids in Epilepsy Treatment: Novel Approaches and Recent Advances

“…Each of these channels contains further, more specific receptors with demonstrated activity relating to the ECS. Research has also demonstrated that broader ECS communication can be mediated by peroxisome-proliferator-activated receptors (PPARs) [ 53 , 54 ]). These nuclear hormone receptors control the transcription of specific genes.…”