The ingestion of food activates mechanisms leading to inhibition of food intake mediated by release of regulatory peptides eg cholecystokinin (CCK) and the lipid amide oleylethanolamide from the gut. In addition, there are both peptides eg ghrelin and lipid amides eg anandamide, that appear to signal the absence of food in the gut and that are associated with stimulation of food intake. Vagal afferent neurons are a common target for both types of signal. Remarkably, the neurochemical phenotype of these neurons itself depends on nutritional status. Dietary fat and protein stimulate CCK release which in turn acts at CCK1 receptors on vagal afferent neurons to inhibit food intake and gastric emptying. It also stimulates expression in these neurons of Y2- receptors and the neuropeptide CART, both of which are associated with inhibition of food intake. Conversely, in fasted rats when plasma CCK is low, these neurons express cannabinoid (CB)-1 and melanin concentrating hormone (MCH)-1 receptors, and MCH, and these are inhibited by exogenous CCK or endogenous CCK released by refeeding. The stimulation of CART expression by CCK is mediated by activation of CREB and EGR1; ghrelin inhibits the action of CCK by promoting nuclear exclusion of CREB and leptin potentiates the action of CCK by stimulation of EGR1 expression. Vagal afferent neurons therefore constitute a level of integration outside the CNS for nutrient-derived signals that control energy intake and that are capable of encoding recent nutrient ingestion.