Lack of Ghrelin Secretion in Response to Fasting in Cholecystokinin-A (-1), -B (-2) Receptor–Deficient Mice

Abstract

Cholecystokinin receptors (CCK-Rs) have been classified into two subtypes: CCK-AR (1R) and -BR (2R). We generated CCK-AR(-/-), CCK-BR(-/-), and CCK-AR(-/-)BR(-/-) mice and found that the gastric emptying of a liquid meal was increased in CCK-BR(-/-) and AR(-/-)BR(-/-) mice, compared with wild-type and CCK-AR(-/-) mice. Given that enhanced gastric emptying leads to eating, food intake after overnight fasting was examined, as was the effect of CCK-8S on food intake. Male mice 6-8 months of age were deprived of food for 16 h with free access to water, after which they were injected intraperitoneally (0.1 ml/mouse) with either vehicle or CCK-8 (0.3, 1.0, or 3.0 nmol/mouse), and their food intake was monitored for 4 h. CCK-8S inhibited food intake in wild-type and CCK-BR(-/-) mice, but not in CCK-AR(-/-) or AR(-/-)BR(-/-) mice. Unexpectedly, we observed a lower food intake in CCK-AR(-/-)BR (-/-) mice treated with vehicle than in mice of the other genotypes. To examine the mechanism of decrease in food intake in CCK-AR(-/-)BR(-/-) mice, the involvement of ghrelin was determined in wild-type and CCK-AR(-/-)BR(-/-) mice. Fasting plasma ghrelin levels were significantly lower in CCK-AR (-/-)BR(-/-) mice than in wild-type mice, and no increase in response to fasting was observed in CCK-AR(-/-)BR(-/-) mice. An administration of acyl-ghrelin produced a small increase in food intake in CCK-AR(-/-)BR(-/-) mice, but not to the levels of wild-type mice. In conclusion, CCK-AR(-/-)BR(-/-) mice showed lower food intake as well as lower response to exogenous ghrelin, and a lower plasma ghrelin level after fasting, though which receptor is more important is unknown.