Identification and characterization of phytocannabinoids as novel dual PPARα/γ agonists by a computational and in vitro experimental approach

Background: The nuclear Peroxisome Proliferator Activated Receptors (PPARs) are ligand-activated transcription factors playing a fundamental role in energy homeostasis and metabolism. Consequently, functional impairment or dysregulation of these receptors lead to a variety of metabolic diseases. While some phytocannabinoids (pCBs) are known to activate PPAR gamma, no data have been reported so far on their possible activity at PPAR alpha. Methods: The putative binding modes of pCBs into PPAR alpha/gamma Ligand Binding Domains were found and assessed by molecular docking and molecular dynamics. Luciferase assays validated in silico predictions whereas the biological effects of such PPAR alpha/gamma ligands were assessed in HepG2 and 3T3L1 cell cultures. Results: The in silico study identified cannabigerolic acid (CBGA), cannabidiolic acid (CBDA) and cannabigerol (CBG) from C. sativa as PPAR alpha/gamma dual agonists, suggesting their binding modes toward PPAR alpha/gamma isoforms and predicting their activity as full or partial agonists. These predictions were confirmed by luciferase functional assays. The resulting effects on downstream gene transcription in adipocytes and hepatocytes were also observed, establishing their actions as functional dual agonists. Conclusions: Our work broadens the activity spectrum of CBDA, CBGA and CBG by providing evidence that these pCBs act as dual PPAR alpha/gamma agonists with the ability to modulate the lipid metabolism. General significance: Dual PPAR alpha/gamma agonists have emerged as an attractive alternative to selective PPAR agonists to treat metabolic disorders. We identified some pCBs as dual PPAR alpha/gamma agonists, potentially useful for the treatment of dyslipidemia and type 2 diabetes mellitus.