Cannabinoid type-1 receptors in CaMKII neurons drive impulsivity in pathological eating behavior

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• dc.contributor.author Martín García, Elena, 1975-
• dc.contributor.author Domingo Rodriguez, Laura, 1992-
• dc.contributor.author Lutz, Beat
• dc.contributor.author Maldonado, Rafael, 1961-
• dc.contributor.author Ruiz de Azua, Iñigo
• dc.date.available 2025-02-21T07:14:11Z
• dc.date.issued 2025
• dc.description.abstract Objectives: Overconsumption of palatable food and energy accumulation are evolutionary mechanisms of survival when food is scarce. These innate mechanisms becom detrimental in obesogenic environment promoting obesity and related comorbidities, including mood disorders. This study aims at elucidating the role of the endocannabinoid system in energy accumulation and hedonic feeding. Methods: We applied a genetic strategy to reconstitute cannabinoid type-1 receptor (CB1) expression at functional levels specifically in CaMKII+ neurons (CaMKII-CB1-RS) and adipocytes (Ati-CB1-RS), respectively, in a CB1 deficient background. Results: Rescued CB1 expression in CaMKII+ neurons, but not in adipocytes, promotes feeding behavior, leading to fasting-induced hyperphagia, increased motivation, and impulsivity to palatable food seeking. In a diet-induced obesity model, CB1 re-expression in CaMKII+ neurons, but not in adipocytes, compared to complete CB1 deficiency, was sufficient to largely restore weight gain, food intake without any effect on glucose intolerance associated with high-fat diet consumption. In a model of glucocorticoid-mediated metabolic syndrome, CaMKII-CB1-RS mice showed all metabolic alterations linked to the human metabolic syndrome except of glucose intolerance. In a binge-eating model mimicking human pathological feeding, CaMKII-CB1-RS mice showed increased seeking and compulsive behavior to palatable food, suggesting crucial roles in foraging and an enhanced susceptibility to addictive-like eating behaviors. Importantly, other contingent behaviors, including increased cognitive flexibility and reduced anxiety-like behaviors, but not depressive-like behaviors, were also observed. Conclusions: CB1 in CaMKII+ neurons is instrumental in feeding behavior and energy storage under physiological conditions. The exposure to risk factors (hypercaloric diet, glucocorticoid dysregulation) leads to obesity, metabolic syndrome, binge-eating and food addiction.
• dc.description.sponsorship This work was supported by CRC1193 “Neurobiology of resilience” to B.L.; EU-FP7 REPROBESITY (HEALTHF2- 2008-223713 to B.L.); Spanish “Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación (AEI)” (PID2020- 120029GB-I00/MICIN/AEI/10.13039/501100011033, RD21/0009/0019 and PDI2023-1511680B-C21), the Spanish “Instituto de Salud Carlos III, RETICS-RTA” (#RD12/0028/0023), the “Generalitat de Catalunya, AGAUR” (#2017 SGR-669), “ICREA-Acadèmia” (#2015) and the Spanish “Ministerio de Sanidad, Servicios Sociales e Igualdad”, “Plan Nacional Sobre Drogas of the Spanish Ministry of Health” (#PNSD-2017I068) to R.M., "la Caixa Health" LCR/PR/HR22/5240017 to R.M. and E.M-G., “Plan Nacional Sobre Drogas of the Spanish Ministry of Health” (#PNSD-2019I006, #PNSD-2023I040) and Spanish “Ministerio de Ciencia e Innovación” (ERA-NET) PCI2021-122073-2A to E.M-G.
• dc.format.mimetype application/pdf
• dc.identifier.citation Martin-Garcia E, Domingo-Rodriguez L, Lutz B, Maldonado R, Ruiz de Azua I. Cannabinoid type-1 receptors in CaMKII neurons drive impulsivity in pathological eating behavior. Mol Metab. 2025 Feb;92:102096. DOI: 10.1016/j.molmet.2025.102096
• dc.identifier.doi http://dx.doi.org/10.1016/j.molmet.2025.102096
• dc.identifier.issn 2212-8778
• dc.identifier.uri http://hdl.handle.net/10230/69669
• dc.language.iso eng
• dc.publisher Elsevier
• dc.relation.ispartof Mol Metab. 2025 Feb;92:102096
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/223713
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2020-120029GB-I00
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PDI2023-1511680B-C21
• dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PCI2021-122073-2A
• dc.rights © 2025 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Cannabinoid type 1 receptor (CB1)
• dc.subject.keyword Endocannabinoid system
• dc.subject.keyword Feeding behavior
• dc.subject.keyword Food addiction
• dc.subject.keyword Impulsivity
• dc.subject.keyword Metabolic syndrome
• dc.subject.keyword Obesity
• dc.title Cannabinoid type-1 receptors in CaMKII neurons drive impulsivity in pathological eating behavior
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion