AIMS: The activation of CB1 receptor (CB1R) is reported to favor energy accumulation and promote resiliency against stress. The aim of this study is to elucidate whether CB1R expression in CaMKII+ neurons is sufficient to restore its role in the regulation of energy metabolism and contingent behaviors.METHODS: To this end, we applied a genetic strategy to reconstitute CB1R expression at endogenous levels in CaMKII+ neurons (CaMKII-CB1-RS).RESULTS: The rescue of CB1R expression in these neurons promotes feeding behavior causing fasting-induced hyperphagia, increased motivation and impulsivity to palatable food seeking. In a diet-induced obesity model, re-expression of CB1R in CaMKII+ neurons was sufficient to largely restored normal body weight gain, food intake but not 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 but, importantly, not glucose intolerance. Finally, in a binge-eating model, CamKII-CB1-RS mice showed an increased palatable food seeking and compulsive behavior to palatable food intake as compared to wild-type mice, suggesting a fundamental role in foraging but also a higher susceptibility to addictive-like eating behaviors. Importantly, this main function also regulates other contingent behaviors increasing cognitive flexibility, reducing anxiety-like behaviors but not depressive-like behaviors.CONCLUSIONS: These findings put forward the notion of the CB1R expression in CaMKII neurons is instrumental in endocannabinoid-mediated feeding behavior and energy storage and, under hypercaloric or glucocorticoid dysregulation conditions lead to obesity, metabolic syndrome, binge-eating disorders and food addiction.