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Tetrahydrocannabinolic Acid a (THCA-A) Reduces Adiposity and Prevents Metabolic Disease Caused by Diet-Induced Obesity

Belén Palomares, Francisco Ruiz-Pino, Martin Garrido-Rodriguez, M. Eugenia Prados, Miguel A. Sánchez-Garrido, Inmaculada Velasco, María J. Vazquez, Xavier Nadal, Carlos Ferreiro-Vera, Rosario Morrugares, Giovanni Appendino, Gaetano Morello, View ORCID ProfileMarco A Calzado, View ORCID ProfileManuel Tena-Sempere, View ORCID ProfileEduardo Muñoz
doi: https://doi.org/10.1101/622035
Belén Palomares
1Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
2Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain
3Hospital Universitario Reina Sofía, Córdoba, Spain
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Francisco Ruiz-Pino
1Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
2Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain
3Hospital Universitario Reina Sofía, Córdoba, Spain
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Martin Garrido-Rodriguez
1Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
4Innovative Health Group, Madrid
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M. Eugenia Prados
5Emerald Health Biotechnology España, Córdoba, Spain
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Miguel A. Sánchez-Garrido
1Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
2Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain
3Hospital Universitario Reina Sofía, Córdoba, Spain
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Inmaculada Velasco
1Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
2Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain
3Hospital Universitario Reina Sofía, Córdoba, Spain
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María J. Vazquez
1Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
2Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain
3Hospital Universitario Reina Sofía, Córdoba, Spain
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Xavier Nadal
6Phytoplant Research, Córdoba, Spain
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Carlos Ferreiro-Vera
6Phytoplant Research, Córdoba, Spain
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Rosario Morrugares
1Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
2Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain
3Hospital Universitario Reina Sofía, Córdoba, Spain
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Giovanni Appendino
7Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Novara, Italy
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Gaetano Morello
8Emerald Health Naturals, Vancouver, Canada
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Marco A Calzado
1Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
2Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain
3Hospital Universitario Reina Sofía, Córdoba, Spain
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  • ORCID record for Marco A Calzado
Manuel Tena-Sempere
1Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
2Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain
3Hospital Universitario Reina Sofía, Córdoba, Spain
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Eduardo Muñoz
1Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
2Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain
3Hospital Universitario Reina Sofía, Córdoba, Spain
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  • ORCID record for Eduardo Muñoz
  • For correspondence: fi1muble@uco.es
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ABSTRACT

Cannabis has remarkable therapeutic potential, but its clinical use is limited by the psychotropic activity of Δ9-tetrahydrocannabinol (Δ9-THC). Surprisingly, the biological profile of the non-narcotic native precursor of Δ9-THC (Δ9-THC acid A, Δ9-THCA-A) is still largely unexplored. 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 with an enhanced osteoblastogenic activity in human mesenchymal stem cells. 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 at inguinal white adipose tissue (iWAT) from mice treated with Δ9-THCA-A confirmed its mode of action on PPARγ. Administration of Δ9-THCA-A in a mouse model of high fat diet (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. Altogether, 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. These findings suggest that Δ9-THCA-A, and perhaps non-decarboxylated Cannabis sativa extracts, are worth considering for addition to our inventory of cannabis medicines.

SIGNIFICANCE STATEMENT The medicinal use of Cannabis is gaining momentum, despite the adverse psychotropic effects of Δ9-THC, the decarboxylation product of its naturally occurring and non-psychotropic precursor Δ9-THCA-A. We present evidence that Δ9-THCA-A is a partial ligand agonist of PPARγ with lower adipogenic activity compared to the full PPARγ agonist rosiglitazone (RGZ). Moreover, chronic administration of Δ9-THCA-A in a mouse model of high fat diet (HFD)-induced obesity significantly reduced body weight gain and fat mass, improved glucose intolerance and insulin resistance, and prevented liver steatosis and macrophage infiltration in fat tissues, additionally inducing white adipose tissue browning. Collectively, these observations qualify Δ9-THCA-A, a compound devoid of psychotropic effects, as an efficacious pharmacological agent to manage metabolic syndrome and obesity-associated inflammation.

Highlights

  • - Δ9-THCA-A is a partial PPARγ ligand agonist with low adipogenic activity

  • - Δ9-THCA-A enhances osteoblastogenesis in bone marrow derived mesenchymal stem cells.

  • - Δ9-THCA-A reduces body weight gain, fat mass, and liver steatosis in HFD-fed mice

  • - Δ9-THCA-A improves glucose tolerance, insulin sensitivity, and insulin profiles in vivo

  • - Δ9-THCA-A induces browning of iWAT and has a potent anti-inflammatory activity

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 29, 2019.
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Tetrahydrocannabinolic Acid a (THCA-A) Reduces Adiposity and Prevents Metabolic Disease Caused by Diet-Induced Obesity
Belén Palomares, Francisco Ruiz-Pino, Martin Garrido-Rodriguez, M. Eugenia Prados, Miguel A. Sánchez-Garrido, Inmaculada Velasco, María J. Vazquez, Xavier Nadal, Carlos Ferreiro-Vera, Rosario Morrugares, Giovanni Appendino, Gaetano Morello, Marco A Calzado, Manuel Tena-Sempere, Eduardo Muñoz
bioRxiv 622035; doi: https://doi.org/10.1101/622035
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Tetrahydrocannabinolic Acid a (THCA-A) Reduces Adiposity and Prevents Metabolic Disease Caused by Diet-Induced Obesity
Belén Palomares, Francisco Ruiz-Pino, Martin Garrido-Rodriguez, M. Eugenia Prados, Miguel A. Sánchez-Garrido, Inmaculada Velasco, María J. Vazquez, Xavier Nadal, Carlos Ferreiro-Vera, Rosario Morrugares, Giovanni Appendino, Gaetano Morello, Marco A Calzado, Manuel Tena-Sempere, Eduardo Muñoz
bioRxiv 622035; doi: https://doi.org/10.1101/622035

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