The endocrine cells of the gut constitute a luminal surveillance system selectively responding to either the presence or absence of food in the gut lumen. Collectively, their secretory products regulate the course of digestion and determine nutrient delivery to the gut by controlling food intake. In both cases the CNS is a major target. Although some gut regulatory peptides may act directly on CNS neurons, there is an established body of evidence to indicate activation of CNS pathways as a consequence of stimulation of vagal afferent neurons. Important consequences of stimulation of these neurons after a meal include inhibition of food intake and activation of autonomic reflexes regulating gastric and pancreatic secretion, gut motility, intestinal immune responses and gastric cytoprotection. Vagal afferent neurons express receptors for intestinal satiety peptides such as cholecystokinin (CCK), GLP-1 and PYY3-36 ie CCK1R, GLP1R and Y2R, respectively. Cholecystokinin stimulates vagal afferent neuron discharge; this effect is potentiated by leptin and by gastric distension, and inhibited by the gastric orexigenic peptide ghrelin. In addition, CCK controls the expression of both G-protein coupled receptors and peptide neurotransmitters by vagal afferent neurons. When plasma CCK concentrations are low, for example after fasting, the expression by these neurons of cannabinoid (CB)1 and melanin concentrating hormone (MCH)1 receptors is increased, as is that of the neuropeptide transmitter MCH; all three are associated with stimulation of food intake. Secretion of CCK leads to a rapid down-regulation of expression of CB1, MCH1R and MCH and to increased expression of Y2R and of the neuropeptide transmitter, cocaine and amphetamine regulated transcript (CARTp), both of which are associated with inhibition of food intake (1-3). Ghrelin blocks these actions of CCK at least in part by excluding phosphoCREB from the nucleus. Thus, vagal afferent neurons (a) are capable of integrating different peripheral signals known to control food intake and (b) exhibit different neurochemical states depending on previous nutrient ingestion. In the fasted state there is enhanced capacity for orexigenic signalling and in the fed state there is enhanced capacity for anorexic signalling. Cholecystokinin acts as a gatekeeper switching vagal afferent neurons between these states and so determining their capacity to respond to other signalling molecules produced by the gastrointestinal tract.