RNA-Seq analysis of inguinal white adipose tissue (iWAT) from control and high fat diet mice treated with THCA and THCA+T007

Medicinal cannabis has garnered worldwide attention in recent years but has been hampered by the psychotropic activity of ?9-tetrahydro-cannabinol (?9-THC). However, the biological activity of its precursor ?9-THC acid (?9-THCA) remain largely unexplored; yet, it is known that ?9-THCA is not psychotropic and displays PPARg agonistic activity. We report here that ?9-THCA is a partial and selective PPARg, albeit with lower adipogenic activity than the full PPARg agonist, rosiglitazone (RGZ). In addition, ?9-THCA enhanced osteoblastogenesis in human mesenchymal stem cells. Docking and in vitro functional assays indicated that ?9-THCA binds and activated PPARg by acting at both the canonical and the alternative binding sites in the PPARg ligand-binding pocket. Indeed, transcriptomic signature at inguinal white adipose tissue (iWAT) from mice treated with ?9-THCA confirmed its mode of action at PPARg. Administration of ?9-THCA for 3-weeks in a mouse model of high fat diet (HFD)-induced obesity significantly reduced fat mass and body weight gain, and markedly ameliorated glucose intolerance and insulin resistance, while largely preventing liver steatosis, adipogenesis and macrophage infiltration in fat tissues. In addition, immunohistochemistry, transcriptomic and plasmatic biomarkers analyses showed that treatment with ?9-THCA caused browning of iWAT and displayed potent anti-inflammatory actions in HFD mice. Altogether, our studies collectively document the potent biological activity of ?9-THCA as a PPARggonist with capacity to substantially improve metabolic syndrome and inflammation associated to obesity. Our findings also imply that non-decarboxylated, Cannabis sativa extracts could be added to the arsenal of cannabis preparations already available in countries where medicinal cannabis is authorized. Overall design: RNA-Seq profiles were generated for C57BL6 mice in five conditions: Control, THCA, THCA+T007, HFD and HFD+THCA (N=2).