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 Δ9-tetrahydro-cannabinol (Δ9-THC). However, the biological activity of its precursor Δ9-THC acid (Δ9-THCA) remain largely unexplored; yet, it is known that Δ9-THCA is not psychotropic and displays PPARg agonistic activity. We report here that Δ9-THCA is a partial and selective PPARg, albeit with lower adipogenic activity than the full PPARg agonist, rosiglitazone (RGZ). In addition, Δ9-THCA enhanced osteoblastogenesis in human mesenchymal stem cells. Docking and in vitro functional assays indicated that Δ9-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 Δ9-THCA confirmed its mode of action at PPARg. Administration of Δ9-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 Δ9-THCA caused browning of iWAT and displayed potent anti-inflammatory actions in HFD mice. Altogether, our studies collectively document the potent biological activity of Δ9-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. RNA-Seq profiles were generated for C57BL6 mice in five conditions: Control, THCA, THCA+T007, HFD and HFD+THCA (N=2).