Nutrient delivery to the gut activates neuroendocrine mechanisms that control digestion and energy intake and utilisation. These include the release from enteroendocrine cells of mediators including 5HT, CCK, GLP-1, PYY and ghrelin that act on vagal afferent neurons regulating food intake and autonomic reflexes controlling motility, secretion, inflammatory responses and mucosal defence. The mediators may act locally on vagal afferent fibres running close to their cell of origin, or distally after delivery in the circulation. Recent work indicates that the signalling mechanisms are strongly influenced by nutrient status. Thus, both food withdrawal and diet-induced obesity alter the sensitivity of vagal afferent neurons to stimulation as well as their patterns of expression of receptors and neuropeptide transmitters. Normally, leptin potentiates vagal afferent stimulation by CCK but this is lost in obesity. Recent studies suggest changes in the gut microbiota in obesity lead to increased LPS which suppresses leptin effects on vagal afferent neurons. There are obvious limitations to direct studies of vagal afferent signalling in man but recent work indicates fMRI brain imaging of CNS responses to CCK and ghrelin is feasible, informative and provides opportunities for future progress in human studies of gut-brain signalling.