The cannabinoid receptor 1 (CB 1R) is required for body weight homeostasis and normal gastrointestinal motility. However, the specific cell types expressing CB 1Rthat regulate these physiological functions are unknown. CB 1Ris widely expressed, including in neurons of the parasympathetic branches of the autonomic nervous system. The vagus nerve has been implicated in the regulation of several aspects of metabolism and energy balance (e.g., food intake and glucose balance), and gastrointestinal functions including motility. To directly test the relevance of CB 1R in neurons of the vagus nerve on metabolic homeostasis and gastrointestinal motility, we generated and characterized mice lacking CB 1R in afferent and efferent branches of the vagus nerve (Cnr1 flox/flox; Phox2b-Cre mice). On a chow or on a high-fat diet, Cnr1 flox/flox; Phox2b-Cre mice have similar body weight, food intake, energy expenditure, and glycemia compared with Cnr1 flox/flox control mice. Also, fasting-induced hyperphagia and after acute or chronic pharmacological treatment with SR141716 [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole carboxamide] (CB 1R inverse agonist) paradigms, mutants display normal body weight and food intake. Interestingly, Cnr1 flox/flox; Phox2b-Cre mice have increased gastrointestinal motility compared with controls. These results unveil CB 1R in the vagus nerve as a key component underlying normal gastrointestinal motility.
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