UC Riverside

The endocannabinoid system (ECS) exerts control over energy homeostasis via interactions between lipid messengers called endocannabinoids (eCBs) and cannabinoid receptors. ECS components are abundant in the CNS and the gastrointestinal (GI) tract. Bi-directional communication between the CNS and GI tract occurs via the vagus nerve. Dysregulation of vagal signaling is associated with adverse physiological and psychological outcomes, such as obesity and anxiety disorders, respectively. We previously showed that eCBs in the GI tract of obese rodents are elevated and drive feeding through peripheral cannabinoid receptor activation. Here, we examined the effects of diet-induced obesity (DIO) on efferent vagus nerve signaling and intestinal eCB formation. We tested the hypothesis that elevated parasympathetic signaling by the efferent vagus is the source of the elevated eCB content and hyperphagia observed in obese mice. We first measured cFos immunoreactivity in the dorsal motor nucleus (DMV) of the efferent vagus in DIO mice. Next, we tested the effects of treatment with muscarinic acetylcholine receptor (mAChR) antagonists on intestinal eCB formation, eCB synthetic enzyme activity, and food intake. Finally, we utilized our conditional intestinal epithelium-specific cannabinoid receptor subtype-1 (CB1R) knockout model (IntCB1-/-) to elucidate the role of intestinal CB1Rs in this process. DMV neuronal activation was significantly elevated in DIO mice compared to lean controls. Treatment with mAChR antagonists reduced intestinal eCB levels, eCB synthetic enzyme activity, and caloric intake in DIO animals. Furthermore, we showed that intestinal CB1Rs are required for mAChR antagonist-induced attenuation of food intake. To evaluate the contribution of intestinal ECS components to the expression of anxious behaviors, we subjected IntCB1-/- male and female mice to a battery of behavioral tests. We quantified circulating corticosterone (CORT) levels at baseline and immediately following behavioral testing. IntCB1-/- male mice exhibited an anxiolytic phenotype that was absent in females. These sex differences were associated with a significant increase in plasma CORT levels for female mice at both time points, regardless of genotype. This body of work reveals a previously unidentified role for the vagus nerve in the context of DIO and behavioral anxiety and highlights critical contributions of the ECS to gut-brain signaling.