Leptin and Neuroendocrine Gene Regulation in Obesity

描述(由申请人提供)： 这项建议的长期目标是了解神经内分泌对能量稳态的调节，以及随着减肥和瘦素应用而发生的神经内分泌轴的变化。特别关注的是下丘脑黑素皮质素和多巴胺能通路，以及参与调节食物摄入量的胃肠激素。目标1的目的是描述维持减重对特定神经内分泌轴(下丘脑-垂体-肾上腺、甲状腺和生长激素)的影响，以及长期低剂量瘦素对肥胖者和体重减轻的肥胖者这些轴的影响。这一目标的前提是，减肥伴随着代谢和荷尔蒙的变化，这在一定程度上是由于瘦素循环浓度的下降而有利于减肥的恢复，并且瘦素替代将使这些参数恢复到减肥前的水平。目的2研究胃旁路手术和捆绑手术以及长期胃刺激下与下丘脑黑素皮质素系统(Ghrelin和PYY(3-36))相互作用的胃肠激素循环浓度的变化。这些荷尔蒙对试餐的反应将被测量并与饥饿感和饱腹感相关。目标3的目的是检测多巴胺和抗多巴胺能药物对下丘脑黑素皮质素系统、体重和葡萄糖代谢的影响。目的的第一部分描述了这些药物对大鼠摄食量、体重和成分的影响，以及对大鼠下丘脑POMC和AgRP基因表达的影响。第二部分研究了长效多巴胺激动剂卡麦角林对肥胖人群体重和葡萄糖代谢的影响。这些研究的结果有望进一步了解减肥的生理反应，并帮助开发减肥和保持减轻体重的治疗方法。

DESCRIPTION (provided by applicant): The long-term objectives of this proposal are to understand the neuroendocrine regulation of energy homeostasis and changes in neuroendocrine axes that occur with weight loss and leptin administration. Particular focus is on the hypothalamic melanocortin and dopaminergic pathways and gastrointestinal hormones involved in the regulation of food intake. The objectives of Aim 1 are to characterize the effects of maintenance of a reduced body weight on specific neuroendocrine axes (hypothalamic-pituitary-adrenal, thyroid and growth hormone) as well as the effects of chronic low dose leptin administration on these axes in obese and weight-reduced obese individuals. This Aim is based on the premise that weight loss is accompanied by metabolic and hormonal changes that favor regain of lost weight in part due to decreased circulating concentrations of leptin and that leptin replacement will restore these parameters to those present prior to weight reduction. Aim 2 examines the changes that occur with gastric bypass and banding procedures and long-term gastric stimulation in circulating concentrations of gastrointestinal hormones that interact with the hypothalamic melanocortin system (ghrelin and PYY(3-36)). The response of these hormones to a test meal will be measured and correlated to feelings of hunger and satiety. The objectives of Aim 3 are to examine the effects of dopaminergic and antidopaminergic agents on the hypothalamic melanocortin system, body weight and glucose metabolism. The first part of this Aim characterizes the effects of these agents on food intake, body weight and composition and on Pomc and Agrp gene expression in the rat hypothalamus. The second part of this examines the effects of a long-acting dopamine agonist, cabergoline, on body weight and glucose metabolism in obese humans. Results from these studies are expected to further the understanding of the physiological responses to weight loss and to help target the development of therapies for weight reduction and the maintenance of a reduced body weight.