CSF INSULIN IN THE REGULATION OF FOOD INTAKE

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Direct CNS infusion of insulin, or peripheral of glucose and insulin, decreases food intake and body weight in non-human primates. Since basal plasma insulin levels are correlated with adiposity, and also with insulin in the cerebrospinal fluid (CSF), it is possible that insulin may be an adiposity signal at the CNS, and provides a negative feedback signal to regulate food intake and body weight perhaps acting through the CSF. The long-term goals of the research in this proposal are to elucidate the mechanisms which underlie regulation of CSF insulin uptake and the role of CSF insulin in food intake. The specific aims of the present studies are first, to elucidate whether CNS sensitivity to exogenous insulin, i.e., decreased food intake, changes during growth and development in normal weight and obese animals, and, second, to determine if insulin uptake into the CSF from plasma is altered during growth and development in normal weight and obese rats. The broad significance and health implications of these studies are that behavioral responsivity to both endogenous nd experimental satiety factors may be altered to allow growth and accumulation of adipose tissue, but this pattern of responsivity may change prior to or during the onset of obesity. To elucidate whether CNS behavioral responsivity to insulin changes during growth and development, insulin will be infused into the CNS of male and female rats at several ages, and changes of food intake and body weight will be monitored. If changes of behavior are observed as a function of age or gender, brain insulin binding will be measured to test whether changes of insulin binding may be the mechanism underlying altered behavioral sensitivity. To test whether CNS insulin access is altered as a function of growth and development, CSF and plasma insulin levels will be measured in male and female rats following peripheral infusion of saline or a range of doses of insulin, at several ages. If the relationship between CSF and plasma insulin levels changes as a function of age or gender, insulin binding will be measured in brain capillary preparations, to test whether changes of capillary insulin receptor concentration may be contributing to the altered CNS insulin uptake. Finally, preliminary studies have shown that both behavioral sensitivity to exogenous insulin and insulin uptake by the CS are abnormal in the genetically obese Zucker rat. They will be measured in dietary obese rates to test whether the defects in the brain insulin system of the obese Zucker rat re due to this obesity or to its genetic background. Together, the proposed studies are directed to understand how a putative adiposity signal--insulin--interacts with the CNS during normal growth and development, and to evaluate its potential contribution to the development of obesity.