Cannabinoid type-1 receptors in CaMKII neurons drive impulsivity in pathological eating behavior
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...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-02-01
|
| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877825000031 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832575483818016768 |
|---|---|
| author | Elena Martin-Garcia Laura Domingo-Rodriguez Beat Lutz Rafael Maldonado Inigo Ruiz de Azua |
| author_facet | Elena Martin-Garcia Laura Domingo-Rodriguez Beat Lutz Rafael Maldonado Inigo Ruiz de Azua |
| author_sort | Elena Martin-Garcia |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-d6f30a8d1ebd4ce4870e9e4ad72ca848 |
| institution | Kabale University |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-d6f30a8d1ebd4ce4870e9e4ad72ca8482025-02-01T04:11:59ZengElsevierMolecular Metabolism2212-87782025-02-0192102096Cannabinoid type-1 receptors in CaMKII neurons drive impulsivity in pathological eating behaviorElena Martin-Garcia0Laura Domingo-Rodriguez1Beat Lutz2Rafael Maldonado3Inigo Ruiz de Azua4Laboratory of Neuropharmacology-Neurophar, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003, Barcelona, Spain; Department of Psychobiology and Methodology in Health Sciences, Universitat Autonoma de Barcelona, 08193, Bellatera, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, SpainLaboratory of Neuropharmacology-Neurophar, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003, Barcelona, Spain; Department of Psychobiology and Methodology in Health Sciences, Universitat Autonoma de Barcelona, 08193, Bellatera, SpainLeibniz Institute for Resilience Research, 55122, Mainz, Germany; Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, 55128, Mainz, GermanyLaboratory of Neuropharmacology-Neurophar, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003, Barcelona, Spain; Department of Psychobiology and Methodology in Health Sciences, Universitat Autonoma de Barcelona, 08193, Bellatera, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, SpainLeibniz Institute for Resilience Research, 55122, Mainz, Germany; Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, 55128, Mainz, Germany; Corresponding author. Leibniz Institute for Resilience Research, 55122, Mainz, Germany.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.http://www.sciencedirect.com/science/article/pii/S2212877825000031Endocannabinoid systemCannabinoid type 1 receptor (CB1)ImpulsivityFeeding behaviorObesityMetabolic syndrome |
| spellingShingle | Elena Martin-Garcia Laura Domingo-Rodriguez Beat Lutz Rafael Maldonado Inigo Ruiz de Azua Cannabinoid type-1 receptors in CaMKII neurons drive impulsivity in pathological eating behavior Molecular Metabolism Endocannabinoid system Cannabinoid type 1 receptor (CB1) Impulsivity Feeding behavior Obesity Metabolic syndrome |
| title | Cannabinoid type-1 receptors in CaMKII neurons drive impulsivity in pathological eating behavior |
| title_full | Cannabinoid type-1 receptors in CaMKII neurons drive impulsivity in pathological eating behavior |
| title_fullStr | Cannabinoid type-1 receptors in CaMKII neurons drive impulsivity in pathological eating behavior |
| title_full_unstemmed | Cannabinoid type-1 receptors in CaMKII neurons drive impulsivity in pathological eating behavior |
| title_short | Cannabinoid type-1 receptors in CaMKII neurons drive impulsivity in pathological eating behavior |
| title_sort | cannabinoid type 1 receptors in camkii neurons drive impulsivity in pathological eating behavior |
| topic | Endocannabinoid system Cannabinoid type 1 receptor (CB1) Impulsivity Feeding behavior Obesity Metabolic syndrome |
| url | http://www.sciencedirect.com/science/article/pii/S2212877825000031 |
| work_keys_str_mv | AT elenamartingarcia cannabinoidtype1receptorsincamkiineuronsdriveimpulsivityinpathologicaleatingbehavior AT lauradomingorodriguez cannabinoidtype1receptorsincamkiineuronsdriveimpulsivityinpathologicaleatingbehavior AT beatlutz cannabinoidtype1receptorsincamkiineuronsdriveimpulsivityinpathologicaleatingbehavior AT rafaelmaldonado cannabinoidtype1receptorsincamkiineuronsdriveimpulsivityinpathologicaleatingbehavior AT inigoruizdeazua cannabinoidtype1receptorsincamkiineuronsdriveimpulsivityinpathologicaleatingbehavior |