VCE-004.8, A Multitarget Cannabinoquinone, Attenuates Adipogenesis and Prevents Diet-Induced Obesity

  • Sci Rep. 2018 Oct 31;8(1):16092. doi: 10.1038/s41598-018-34259-0.
Belen Palomares  1  2  3 ,  Francisco Ruiz-Pino  1  2  3 ,  Carmen Navarrete  4 ,  Inmaculada Velasco  1  2  3 ,  Miguel A Sánchez-Garrido  1  2  3 ,  Carla Jimenez-Jimenez  1  2  3 ,  Carolina Pavicic  5 ,  Maria J Vazquez  1  2  3 ,  Giovanni Appendino  6 ,  M Luz Bellido  4  7 ,  Marco A Calzado  1  2  3 ,  Manuel Tena-Sempere  1  2  3 ,  Eduardo Muñoz  8  9  10
Affiliations
  • 1. Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain.
  • 2. Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain.
  • 3. Hospital Universitario Reina Sofía, Córdoba, Spain.
  • 4. Vivacell Biotechnology España, Córdoba, Spain.
  • 5. Innohealth Group, Madrid, Spain.
  • 6. Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Novara, Italy.
  • 7. Emerald Health Pharmaceuticals, San Diego, USA.
  • 8. Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain. [email protected].
  • 9. Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Córdoba, Spain. [email protected].
  • 10. Hospital Universitario Reina Sofía, Córdoba, Spain. [email protected].
PMID: 30382123 DOI: 10.1038/s41598-018-34259-0
Abstract

Over the past few years, the endocannabinoid system (ECs) has emerged as a crucial player for the regulation of food intake and energy metabolism, and its pharmacological manipulation represents a novel strategy for the management of metabolic diseases. The discovery that VCE-004.8, a dual PPARγ and CB2 receptor agonist, also inhibits prolyl-hydroxylases (PHDs) and activates the HIF pathway provided a rationale to investigate its effect in in vitro models of adipogenesis and in a murine model of metabolic syndrome, all processes critically regulated by these targets of VCE-004.8. In accordance with its different binding mode to PPARγ compared to rosiglitazone (RGZ), VCE-004.8 neither induced adipogenic differentiation, nor affected osteoblastogenesis. Daily administration of VCE-004.8 (20 mg/kg) to HFD mice for 3-wks induced a significant reduction in body weight gain, total fat mass, adipocyte volume and plasma triglycerides levels. VCE-004.8 could also significantly ameliorate glucose tolerance, reduce Leptin levels (a marker of adiposity) and increase Adiponectin and incretins (GLP-1 and GIP) levels. Remarkably, VCE-004.8 increased the FGF21 mRNA expression in white and brown adipose, as well as in a BAT cell line, qualifying cannabinoaminoquinones as a class of novel therapeutic candidates for the management of obesity and its common metabolic co-morbidities.

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