CSF INSULIN IN THE REGULATION OF FOOD INTAKE

直接CNS输注胰岛素或外周葡萄糖， 胰岛素，减少非人类的食物摄入量和体重 灵长类动物 由于基础血浆胰岛素水平与 肥胖症，以及脑脊液（CSF）中的胰岛素， 胰岛素可能是中枢神经系统肥胖信号， 并提供负反馈信号以调节食物摄入， 体重可能通过脑脊液起作用。 远景目标 这项研究的目的是阐明 这是调节CSF胰岛素摄取的基础， 胰岛素在食物摄入中的作用 本研究的具体目标 首先，阐明中枢神经系统对外源性 胰岛素，即，食物摄入量减少，生长过程中的变化， 在正常体重和肥胖动物中的发育，第二， 确定从血浆到CSF的胰岛素摄取是否改变 在正常体重和肥胖大鼠的生长和发育过程中。 的 这些研究的广泛意义和健康影响是 对内源性和实验性的行为反应 饱腹感因子可以被改变以允许生长和积累 脂肪组织，但这种反应模式可能会改变之前， 或在肥胖症发作期间。 为了阐明CNS是否 生长期间对胰岛素变化的行为反应， 在发育过程中，胰岛素将被输注到男性的CNS中， 不同年龄雌性大鼠的摄食量和体质量变化 将监测体重。 如果观察到行为变化， 根据年龄或性别，将测量脑胰岛素结合 以测试胰岛素结合的变化是否是 潜在的行为敏感性改变 为了测试CNS是否 胰岛素的获取作为生长和发育的函数而改变， 将测量雄性和雌性动物的CSF和血浆胰岛素水平 外周输注生理盐水或一系列剂量后的大鼠 在不同的年龄段注射胰岛素 如果CSF和 血浆胰岛素水平作为年龄或性别的函数而变化， 将在脑毛细血管制备物中测量胰岛素结合， 检测毛细血管胰岛素受体浓度的变化是否 可能导致中枢神经系统胰岛素摄取改变。 最后， 初步研究表明，行为敏感性， CS的外源性胰岛素和胰岛素摄取在 遗传性肥胖的Zucker鼠 他们将在饮食测量 肥胖率来测试大脑胰岛素系统的缺陷是否 肥胖的Zucker大鼠的死亡率是由于肥胖还是遗传 背景 建议的研究旨在 了解一个假定的肥胖信号--胰岛素--是如何与 正常生长和发育期间的CNS，并评估其 对肥胖症的发展有潜在的贡献。

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.