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 PPARγ, no data have been reported so far on their possible activity at PPARα. METHODS: The putative binding modes of pCBs into PPARα/γ 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 PPARα/γ 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 PPARα/γ dual agonists, suggesting their binding modes toward PPARα/γ 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 PPARα/γ agonists with the ability to modulate the lipid metabolism. GENERAL SIGNIFICANCE: Dual PPARα/γ agonists have emerged as an attractive alternative to selective PPAR agonists to treat metabolic disorders. We identified some pCBs as dual PPARα/γ agonists, potentially useful for the treatment of dyslipidemia and type 2 diabetes mellitus.