Tetrahydrocannabinolic acid A (THCA-A) reduces adiposity and prevents metabolic disease caused by diet-induced obesity

Medicinal cannabis has remarkable therapeutic potential, but its clinical use is limited by the psychotropic activity of \u3949-tetrahydrocannabinol (\u3949-THC). However, the biological profile of the carboxylated, non-narcotic native precursor of \u3949-THC, the \u3949-THC acid A (\u3949-THCA-A), remains largely unexplored. Here we present evidence that \u3949-THCA-A is a partial and selective PPAR\u3b3 modulator, endowed with lower adipogenic activity than the full PPAR\u3b3 agonist rosiglitazone (RGZ) and enhanced osteoblastogenic effects in hMSC. Docking and in vitro functional assays indicated that \u3949-THCA-A binds to and activates PPAR\u3b3 by acting at both the canonical and the alternative sites of the ligand-binding domain. Transcriptomic signatures in iWAT from mice treated with \u3949-THCA-A confirmed its mode of action through PPAR\u3b3. Administration of \u3949-THCA-A in a mouse model of HFD-induced obesity significantly reduced fat mass and body weight gain, markedly ameliorating glucose intolerance and insulin resistance, and largely preventing liver steatosis, adipogenesis and macrophage infiltration in fat tissues. Additionally, immunohistochemistry, transcriptomic, and plasma biomarker analyses showed that treatment with \u3949-THCA-A caused browning of iWAT and displayed potent anti-inflammatory actions in HFD mice. Our data validate the potential of \u3949-THCA-A as a low adipogenic PPAR\u3b3 agonist, capable of substantially improving the symptoms of obesity-associated metabolic syndrome and inflammation