Search

Food intake and body weight are determined by a complex interaction of regulatory pathways. To elucidate the contribution of the endogenous peptide cholecystokinin, mice lacking functional cholecystokinin-A receptors were generated by targeted gene disruption. To explore the role of the cholecystokinin-A receptor in mediating satiety, food intake of cholecystokinin-A receptor-/- mice was compared with the corresponding intakes of wild-type animals and mice lacking the other known cholecystokinin receptor subtype, cholecystokinin-B/gastrin. Intraperitoneal administration of cholecystokinin failed to decrease food intake in mice lacking cholecystokinin-A receptors. In contrast, cholecystokinin diminished food intake by up to 90% in wild-type and cholecystokinin-B/gastrin receptor-/- mice. Together, these findings indicate that cholecystokinin-induced inhibition of food intake is mediated by the cholecystokinin-A receptor. To explore the long-term consequences of either cholecystokinin-A or cholecystokinin-B/gastrin receptor absence, body weight as a function of age was compared between freely fed wild-type and mutant animals. Both cholecystokinin-A and cholecystokinin-B/gastrin receptor-/- mice maintained normal body weight well into adult life. In addition, each of the two receptor-/- strains had normal pancreatic morphology and were normoglycemic. Our results suggest that although cholecystokinin plays a role in the short-term inhibition of food intake, this pathway is not essential for the long-term maintenance of body weight.

The effects of intake of a palatable food source on oral amphetamine intake were assessed in adult male Long-Evans rats. In Experiment 1, six rats were given an amphetamine sulfate solution (0.1 mg/ml) and four rats were given water as their sole source of fluid. Rats were given a choice of chow and granulated sucrose for a week, alternated with weeks when only chow was fed. In Experiment 2, eight rats were given the amphetamine solution, and four rats water to drink. Rats were fed chow and hydrogenated vegetable fat for a week alternated with weeks when only chow was available. In both experiments, rats drank significantly less of the amphetamine solution when the palatable food choice was available than when given only chow to eat. Intake of palatable foods had a significantly smaller effect on water intake. In both experiments, rats drinking the amphetamine solution took in less fluid and less calories and gained less weight than rats drinking water. However, in Experiment 1, when sucrose was available, rats drinking amphetamine consumed a significantly greater proportion of their calories as sucrose than rats drinking water. Similarly, in Experiment 2, rats drinking the amphetamine solution chose a significantly greater percentage of their calories as fat than rats drinking water. These results demonstrate that intake of sucrose or fat leads to a significant reduction in amphetamine intake, and that the anorectic effects of amphetamine are not equivalent for different types of foods.

The hypothalamus plays a central role in the integrated regulation of energy homeostasis and body weight, and a number of hypothalamic neuropeptides, such as neuropeptide Y (ref. 1), galanin, CRH (ref. 3) and GLP-1 (ref. 4), have been implicated in the mediation of these effects. To discover new hypothalmic peptides involved in the regulation of body weight, we used differential display polymerase chain reaction to identify messenger RNAs that are differentially expressed in the hypothalamus of ob/+ compared with ob/ob C57B1/6J mice. We show here that one mRNA that is overexpressed in the hypothalamus of ob/ob mice encodes the neuropeptide melanin-concentrating hormone (MCH). Fasting further increased expression of MCH mRNA in both normal and obese animals. Neurons containing MCH are located in the zona incerta and in the lateral hypothalamus. These areas are involved in regulation of ingestive behaviour, but the role of MCH in mammalian physiology is unknown. To determine whether MCH is involved in the regulation of feeding, we injected MCH into the lateral ventricles of rats and found that their food consumption increased. These findings suggest that MCH participates in the hypothalamic regulation of body weight.