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Biochem Pharmacol. 2019 Nov 9;171:113693. doi: 10.1016/j.bcp.2019.113693. [Epub ahead of print]

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

Author information

1
Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba 14004, Spain; Department of Cellular Biology, Physiology and Immunology, University of Córdoba, Córdoba; University Hospital Reina Sofía, Córdoba, Spain.
2
Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba 14004, Spain; Innovative Health Group, Madrid, Spain.
3
Emerald Health Biotechnology España, Córdoba, Spain.
4
Phytoplant Research, Córdoba, Spain.
5
Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Novara, Italy.
6
Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba 14004, Spain; Department of Cellular Biology, Physiology and Immunology, University of Córdoba, Córdoba; University Hospital Reina Sofía, Córdoba, Spain. Electronic address: fi1muble@uco.es.

Abstract

Medicinal cannabis has remarkable therapeutic potential, but its clinical use is limited by the psychotropic activity of Δ9-tetrahydrocannabinol (Δ9-THC). However, the biological profile of the carboxylated, non-narcotic native precursor of Δ9-THC, the Δ9-THC acid A (Δ9-THCA-A), remains largely unexplored. Here we present evidence that Δ9-THCA-A is a partial and selective PPARγ modulator, endowed with lower adipogenic activity than the full PPARγ agonist rosiglitazone (RGZ) and enhanced osteoblastogenic effects in hMSC. Docking and in vitro functional assays indicated that Δ9-THCA-A binds to and activates PPARγ by acting at both the canonical and the alternative sites of the ligand-binding domain. Transcriptomic signatures in iWAT from mice treated with Δ9-THCA-A confirmed its mode of action through PPARγ. Administration of Δ9-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 Δ9-THCA-A caused browning of iWAT and displayed potent anti-inflammatory actions in HFD mice. Our data validate the potential of Δ9-THCA-A as a low adipogenic PPARγ agonist, capable of substantially improving the symptoms of obesity-associated metabolic syndrome and inflammation.

KEYWORDS:

Cannabis; Inflammation; Obesity; Pparγ; Δ9-THCA-A

PMID:
31706843
DOI:
10.1016/j.bcp.2019.113693

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