Abstract

To elucidate the role of endogenous ghrelin in the regulation of energy homeostasis and gastric emptying, ghrelin knockout mice (ghrelin^-/-) were generated. Body weight, food intake, respiratory quotient, and heat production (indirect calorimetry), and gastric emptying (¹⁴C breath test) were compared between ghrelin^+/+ and ghrelin^-/- mice. In both strains, the effect of exogenous ghrelin on gastric emptying and food intake was determined. Ghrelin^-/- mice showed some subtle phenotypic changes. Body weight gain and 24-h food intake were not affected, but interruption of the normal light/dark cycle triggered additional food intake in old ghrelin^+/+ but not in ghrelin^-/- mice. Exogenous ghrelin increased food intake in both genotypes with a bell-shaped dose-response curve that was shifted to the left in ghrelin^-/- mice. During the dark period, young ghrelin^-/- mice had a lower respiratory quotient, whereas their heat production was higher than that of the wild-type littermates, inferring a leaner body composition of the ghrelin^-/- mice. Absence of ghrelin did not affect gastric emptying, and the bell-shaped dose-response curves of the acceleration of gastric emptying by exogenous ghrelin were not shifted between both strains. In conclusion, ghrelin is not an essential regulator of food intake and gastric emptying, but its loss may be compensated by other redundant inputs. In old mice, meal initiation triggered by the light/dark cue may be related to ghrelin. In young animals, ghrelin seems to be involved in the selection of energy stores and in the partitioning of metabolizable energy between storage and dissipation as heat.