Abstract
Phytocannabinoids (pCBs) are a large family of meroterpenoids isolated from the plant Cannabis sativa. Δ9-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 (PPARγ), a nuclear receptor involved in energy homeostasis and lipid metabolism. In the search of new pCBs potentially acting as PPARγ agonists, we identified cannabimovone (CBM), a structurally unique abeo-menthane pCB, as a novel PPARγ modulator via a combined computational and experimental approach. The ability of CBM to act as dual PPARγ/α 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 PPARγ. Luciferase assays confirmed the computational results, showing a selective activation of PPARγ by CBM in the low micromolar range. CBM promoted the expression of PPARγ 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.
Highlights
Peroxisome proliferation-activated receptors (PPARs) are ligand-activated transcription factors involved in the regulation of energy homeostasis and metabolism [1]
The representative pose from the cluster was chosen to undergo the subsequent molecular dynamics (MD) simulation
THC and CBD, the most representative pCBs, have interesting therapeutic applications due to their complex pharmacological profile, and they are active on the PPARγ receptor, while a few other neutral and acidic pCBs were characterized as dual PPARα/γ agonists [15]
Summary
Peroxisome proliferation-activated receptors (PPARs) are ligand-activated transcription factors involved in the regulation of energy homeostasis and metabolism [1]. The binding of agonists to the PPAR ligand-binding domain (LBD) induces conformational changes, leading to the release of a corepressor and the recruitment of coactivator peptides. The LBD is a 12-helix bundle domain with a central core forming the ligand binding pocket. Three different PPAR isoforms, namely α, γ, and β/δ, were characterized so far [4], with PPARγ playing a crucial role in regulating adipocyte differentiation, lipid metabolism, glucose homeostasis, and insulin resistance [5]. For these reasons, it represents a pharmacological target for the treatment of insulin resistance and dyslipidemia [6,7].
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