Identification of the Ghrelin and Cannabinoid CB₂ Receptor Heteromer Functionality and Marked Upregulation in Striatal Neurons from Offspring of Mice under a High-Fat Diet

• Main Authors: Jaume Lillo, Alejandro Lillo, David A. Zafra, Cristina Miralpeix, Rafael Rivas-Santisteban, Núria Casals, Gemma Navarro, Rafael Franco
• Format: Article
• Language: English
• Published: MDPI AG 2021-08-01
• Series: International Journal of Molecular Sciences
• Subjects: orexigenic; anorexia; marihuana; phytocannabinoids; G protein-coupled receptors; pharmacology
• Online Access: https://www.mdpi.com/1422-0067/22/16/8928
• ISSN: 1661-6596; 1422-0067

Cannabinoids have been reported as orexigenic, i.e., as promoting food intake that, among others, is controlled by the so-called “hunger” hormone, ghrelin. The aim of this paper was to look for functional and/or molecular interactions between ghrelin GHSR1a and cannabinoid CB₂ receptors at the central nervous system (CNS) level. In a heterologous system we identified CB₂-GHSR1a receptor complexes with a particular heteromer print consisting of impairment of CB₂ receptor/G_i-mediated signaling. The blockade was due to allosteric interactions within the heteromeric complex as it was reverted by antagonists of the GHSR1a receptor. Cannabinoids acting on the CB₂ receptor did not affect cytosolic increases of calcium ions induced by ghrelin acting on the GHSR1a receptor. In situ proximity ligation imaging assays confirmed the expression of CB₂-GHSR1a receptor complexes in both heterologous cells and primary striatal neurons. We tested heteromer expression in neurons from offspring of high-fat-diet mouse mothers as they have more risk to be obese. Interestingly, there was a marked upregulation of those complexes in striatal neurons from siblings of pregnant female mice under a high-fat diet.