CONTEXTGhrelin is an orexigenic hormone that can increase body weight. Its circulating levels increase before meals and are suppressed after food ingestion. Understanding the effects of specific types of ingested macronutrients on ghrelin regulation could facilitate the design of weight-reducing diets.OBJECTIVEWe sought to understand how ingestion of carbohydrates, proteins, or lipids affect acyl (bioactive) and total ghrelin levels among human subjects, hypothesizing that lipids might suppress ghrelin levels less effectively than do either carbohydrates or proteins.DESIGNThis was a randomized, within-subjects cross-over study.SETTINGThe study was conducted at a University Clinical Research Center.PARTICIPANTSThere were 16 healthy human subjects included in the study.INTERVENTIONSIsocaloric, isovolemic beverages composed primarily of carbohydrates, proteins, or lipids were provided.MAIN OUTCOME MEASURESThe magnitude of postprandial suppression of total and acyl ghrelin levels (measured with a novel acyl-selective, two-site ELISA) was determined.RESULTSAll beverages suppressed plasma acyl and total ghrelin levels. A significant effect of macronutrient class on decremental area under the curve for both acyl and total ghrelin was observed; the rank order for magnitude of suppression was protein more than carbohydrate more than lipid. Total ghrelin nadir levels were significantly lower after both carbohydrate and protein, compared with lipid beverages. In the first 3 postprandial hours, the rank order for acyl and total ghrelin suppression was carbohydrate more than protein more than lipid. In the subsequent 3 h, there was a marked rebound above preprandial values of acyl and total ghrelin after carbohydrate ingestion alone.CONCLUSIONSThese findings suggest possible mechanisms contributing to the effects of high-protein/low-carbohydrate diets to promote weight loss, and high-fat diets to promote weight gain.