Enteroendocrine cells sense nutritive and non-nutritive properties of luminal food and, in response, release satiation peptides from their basolateral aspect. These signals diffuse through the lamina propria to activate nearby vagal- and spinal-afferent fibers from neurons within the nodose and dorsal root ganglia, respectively, as well as myenteric neurons. Satiation peptides can also enter the bloodstream to act distantly as hormones. Gut-peptide release is regulated not only by luminal nutrients but also by somatic signals. The basolateral side of enteroendocrine cells bears receptors that respond to neurotransmitters, growth factors, and cytokines. Neurotransmitters mediate duodenal-ileal communication to regulate L cell secretion, and they enable central modulation of gut-peptide release. Whether vagal- or spinal-afferent nerves are directly activated by ingested nutrients is uncertain. Although vagal- and spinal-afferent fibers approach the abluminal aspect of enteroendocrine cells and enterocytes, they do not form synapse-like contacts with these epithelial cells, nor do they extend to the intestinal lumen. Some subepithelial nerve fibers might respond to luminal chemicals that diffuse across the epithelium, such as FAs, but this applies only to short-chain FAs, which do not efficiently elicit satiation (116). Other vagal-afferent fibers respond selectively to intestinal carbohydrates or fats. Although it is theoretically possible that these neurons sense nutrients in the extracellular space, it is more clearly established that signaling molecules released from enteroendocrine cells mediate macronutrient-specific neural activation.