Small intestinal receptors play a key role in sensing the arrival of nutrients in the intestinal lumen, initiating feedback loops that lead to adjustments in the rate of gastric emptying and the release of gut hormones, both of which are involved in the regulation of energy intake. Lipid has potent effects on these functions, requiring fat digestion and fatty acids with a chain length of ≥12 carbon atoms. Dietary modifications can influence these effects of fat, so that overconsumption of a high-energy, high-fat diet reduces, while energy restriction enhances, the sensitivity to the gastrointestinal (GI) and appetite-suppressant effects of fat. Moreover, obesity is associated with compromised GI responses to dietary fat. Dietary protein, particularly whey, is considered to be the most satiating macronutrient, an effect that is, in part, also mediated by changes in GI functions, although the effects of protein appear to be less potent than those of lipid. In contrast to lipid, the appetite-suppressant effects of protein appear to remain intact in obesity, so that both isocaloric intraduodenal infusions of protein, or ingestion of a high-protein meal, reduce subsequent energy intake, in both lean and obese individuals. Our recent research, investigating the potential role of specific amino acids in mediating the effects of protein on GI functions and energy intake, has established that certain amino acids, e.g. L-tryptophan and L-leucine, suppress subsequent energy intake, in excess of their own energy content, despite diverse, and relatively modest, or no, effects on GI functions. In contrast, their effects on energy intake were more closely related to their respective plasma concentrations, suggesting that the energy intake-suppressant effects of these amino acids, and protein, may be mediated not primarily by GI effects, but through effects of circulating amino acids. Further research is warranted to identify the mechanisms underlying nutrient-induced appetite suppression to identify novel targets for the treatment and management of obesity.