Cannabinoid type-1 receptors in CaMKII neurons drive impulsivity in pathological eating behavior
Martín-García, Elena 1975- (Universitat Autònoma de Barcelona. Departament de Psicobiologia i de Metodologia de les Ciències de la Salut)
Domingo-Rodriguez, Laura (Universitat Autònoma de Barcelona. Departament de Psicobiologia i de Metodologia de les Ciències de la Salut)
Lutz, Beat (Leibniz Institute for Resilience Research (Magúncia, Alemanya))
Maldonado, Rafael 1961- (Universitat Autònoma de Barcelona. Departament de Psicobiologia i de Metodologia de les Ciències de la Salut)
Ruiz de Azua, Inigo (Leibniz Institute for Resilience Research (Magúncia, Alemanya))

Data:	2025
Resum:	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. 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. 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. 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.
Ajuts:	Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-669 European Commission 223713 Instituto de Salud Carlos III RD21/0009/0019 Instituto de Salud Carlos III RD12/0028/0023 Agencia Estatal de Investigación PID2020-120029GB-I00 Agencia Estatal de Investigación PID2023-151168OB-C21 Ministerio de Sanidad, Servicios Sociales e Igualdad PNSD-2017I068 Ministerio de Sanidad PNSD-2019I006 Ministerio de Sanidad PNSD-2023I040 Ministerio de Ciència e Innovación PCI2021-122073-2A La Caixa Foundation LCR/PR/HR22/5240017
Nota:	Altres ajuts: This work was supported by CRC1193 "Neurobiology of resilience" to B.L.; ICREA-Acadèmia (2015).
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Endocannabinoid system ; Cannabinoid type 1 receptor (CB1) ; Impulsivity ; Feeding behavior ; Obesity ; Metabolic syndrome ; Food addiction
Publicat a:	Molecular metabolism, Vol. 92, art. 102096 (january 2025) , ISSN 2212-8778

DOI: 10.1016/j.molmet.2025.102096
PMID: 39788291

13 p, 3.1 MB

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