As the first point of contact for ingested nutrients, the upper gastrointestinal (GI) tract plays a key role in sensing the characteristics of the ingested meal content and in signaling this information to the brain. The interaction of nutrients with small intestinal nutrient-sensing receptors also triggers the release of gut hormones and initiates feedback loops that lead to adjustments in the rate of gastric emptying, 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 GI and appetite-suppressant effects of fat. Moreover, obesity is associated with compromised GI responses to dietary fat. Dietary protein, particularly whey, is also considered to be a highly satiating macronutrient, an effect that is, in part, mediated by changes in GI functions, although protein appears to have less potent effects to activate GI functions than 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. Such findings are consistent with the efficacy of high-protein diets to achieve significant weight loss. Interestingly, 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. Taken together, the role of the gut in mediating the energy intake-suppressant effects of dietary nutrients appears to vary according to macronutrient class. Moreover, the adaptive changes in GI function that occur in response to a high fat intake may, at least in part, underlie the obesogenic properties of fat.