To elucidate the role of endogenous ghrelin in the regulation of energy homeostasis and gastric emptying, ghrelin knockout mice (ghrelin Ϫ/Ϫ ) were generated. Body weight, food intake, respiratory quotient, and heat production (indirect calorimetry), and gastric emptying ( 14 C breath test) were compared between ghrelin ϩ/ϩ and ghrelin Ϫ/Ϫ mice. In both strains, the effect of exogenous ghrelin on gastric emptying and food intake was determined. Ghrelin Ϫ/Ϫ 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 ϩ/ϩ but not in ghrelin Ϫ/Ϫ mice. Exogenous ghrelin increased food intake in both genotypes with a bell-shaped dose-response curve that was shifted to the left in ghrelin Ϫ/Ϫ mice. During the dark period, young ghrelin Ϫ/Ϫ 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 Ϫ/Ϫ 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.
Obestatin has recently been discovered in the rat stomach. It is encoded by the ghrelin gene and has been claimed to be a functional opponent of ghrelin and to be the natural ligand of the GPR39 receptor. The latter could not be confirmed by Holst et al. (Endocrinology, 2006). Yet, in GPR39 knockout mice, gastric emptying is accelerated. We verified the effects of obestatin on gastric emptying and intestinal contractility in rodents. Gastric emptying was measured with the (14)C octanoic breath test in mice. In vitro, the effect of obestatin was studied on electrically stimulated and non-stimulated strips from the fundus and small intestine of mice and rats. Obestatin (60, 125, 250 nmol kg(-1)) did not affect gastric emptying parameters (T(half) and T(lag)) and did not inhibit the prokinetic effects of ghrelin. Mouse and rat intestinal and fundic smooth muscle strips did not respond to obestatin either in the absence or in the presence of electrical field stimulation. Obestatin (125 nmol kg(-1)) did not inhibit fasting-induced hyperphagia. Our results suggest that peripheral obestatin is not a satiety signal that plays a role in the regulation of gastric emptying and do not support the concept that obestatin is a physiological opponent of ghrelin.
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