Identification and Characterization of Cannabimovone, a Cannabinoid from Cannabis sativa, as a Novel PPARgamma Agonist via a Combined Computational and Functional Study

Phytocannabinoids (PCBs) are a large family of meroterpenoids isolated from the plant Cannabis sativa. D9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the best investigated phytocannabinoids due to their relative abundance and interesting bioactivity profiles. In addition to various targets, THC and CBD are also well-known agonists of peroxisome proliferator-activated receptor gamma (PPARgamma ), a nuclear receptor involved in energy homeostasis and lipid metabolism. In the search of new PCBs potentially acting as PPARalpha agonists, we identified cannabimovone (CBM), a structurally unique abeo-menthane PCB, as a novel PPAR? modulator via a combined computational and experimental approach. The ability of CBM to act as dual PPARalpha/gamma agonist was also evaluated. Computational studies suggested a different binding mode toward the two isoforms, with the compound able to recapitulate the pattern of H-bonds of a canonical agonist only in the case of PPARgamma. Luciferase assays confirmed the computational results, showing a selective activation of PPARgamma by CBM in the low micromolar range. CBM promoted the expression of PPARgamma target genes regulating the adipocyte differentiation and prevented palmitate-induced insulin signaling impairment. Altogether, these results candidate CBM as a novel bioactive compound potentially useful for the treatment of insulin resistance-related disorders.