The presence of nutrients in the intestinal lumen initiates release of regulatory peptides from endocrine cells in the gut wall resulting in a number of signaling events in the epithelium, including activation of extrinsic and intrinsic neurons, and subsequent changes in gastrointestinal function and regulation of food intake. However, the mechanisms that underlie these events are not fully understood. This presentation will review three aspects of this process; 1. the process by which endocrine cells respond to nutrients and the role of different proteins either expressed in the apical membrane of the cells, including G protein coupled receptors and nutrient transporter-related proteins, or intracellular proteins, such as apolipoprotein A-IV; 2. the regulatory peptides released from gut endocrine cells that activate vagal afferent activity via expression of specific receptors for several gut regulatory peptides, including cholecystokinin (CCK) type 1, peptide YY type 2, 5-HT type 3, leptin, ghrelin, cannabinoid type 1, and glucagon-like peptides (GLP)-1 and -2 receptors; 3. the changes in sensitivity of this pathway that lead to changes in gastrointestinal function and dysregulation of food intake, and how these mechanisms and pathways might be altered in diseases, such as inflammation and obesity.