Furthermore, disorders that enhance intestinal endocannabinoid tone, including diet-induced obesity,5 could further exacerbate barrier function and pathology associated with metabolic endotoxemia, which itself has been shown to initiate the onset of diabetes and obesity.78,79 It will be important to further define the specific localization of CB1Rs within the epithelium for the reported effects on barrier function for microbiota–CB1R interactions and to define the role for local immune cells in these processes. Here, CNR1 is linked to obesity due to melanocortin 4 receptor deficiency.