The proposed research will build upon an ongoing program investigating the hormonal controls of food intake, using laboratory rats as a model. Most of the proposed experiments will investigate various aspects of the hypothesis that in the normal regulation of adiposity, the brain is able to determine the fatness of the individual from the level of insulin that it sees. More obese people and animals have more insulin in their blood, and leaner individuals have less insulin. The insulin is hypothesized to cross the blood-brain barrier, perhaps at the brain capillary wall, and thus to gain access to the cerebrospinal fluid (CSF) and brain. Insulin has been measured within the CSF and brain of several species, and the experimental administration of additional insulin into the CSF elicits reduced feeding and loss of body weight, as if the brain were receiving a signal that the body is fatter than it actually is. Specific proposed experiments will determine how this brain insulin system interacts with other factors known to control appetite and meal size, especially other neuropeptides including cholecystokinin (CCK) and neuropeptide Y (NPY). Normal (and in some experiments, genetically obese) rats will be given these neuropeptides in the absence and presence of the administration of exogenous insulin into the CSF to determine if the animals' sensitivity to them is altered. Other experiments will investigate the physiology of the ingestive responses to NPY. In another series of experiments, the ability of insulin to penetrate into the brain and CSF will be determined under normal conditions and in rats which are food-deprived and hence underweight, and in rats rendered obese. The sensitivity of the brain to insulin will also be measured in these experiments, both behaviorally and via estimation of the capacity of brain cells to bind insulin molecules. A final series of proposed experiments will determine if glucocorticoids alter the sensitivity of the brain to insulin, and thereby also impact food intake. The proposed research addresses important questions regarding the interactions of factors known to be important in the control of food intake and the regulation of body weight. It is possible that new therapeutic strategies for the treatment of obesity and/or eating disorders may result.
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