AbstractUnderstanding normal and dysfunctional energy regulation and body weight regulation requires neural evaluation of the signals involved in the control of food intake within a meal, as well as signals related to the availability of stored fuels. Work from our laboratory has focused on peripheral and central nervous system studies of behavior and physiology designed to improve our understanding of the role of gut—brain communication in the control of food intake and energy homeostasis. Gastrointestinal administration of nutrients reduces subsequent meal size, suggesting a potent role for peripheral nutrient sensing in the negative feedback control of ingestion. Vagal afferent nerves supply gastrointestinal sites stimulated during food intake, and these nerves are responsive to mechanical and nutrient chemical properties of ingested food. In addition, the presence of nutrients in these gastrointestinal sites stimulates the release of peptides that affect energy intake. These gut peptides also modulate the activity of peripheral gastrointestinal sensory nerves in ways that may contribute to their effects on food intake. In the central nervous system, adiposity hormones and their downstream mediators have been shown to work at both hindbrain and forebrain sites to affect food intake and metabolism. Importantly, recent data has shown that adiposity hormones acting in the brain increase the behavioral and neural potency of feeding inhibitory gastrointestinal stimuli. These data support the suggestion that insensitivity to adiposity hormones in obesity may be characterized by alterations in their ability to modulate the neural processing of food signals important in determining how much food is consumed during a meal.