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能量稳态的神经内分泌调节和神经内分泌轴的变化，发生与减肥和瘦素管理。特别关注的是下丘脑黑皮质素和多巴胺能途径和胃肠道激素参与调节食物摄入。目的1的目的是表征维持体重减轻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，以及慢性低剂量瘦素给药对肥胖和体重减轻的肥胖个体的这些轴的影响。这一目标是基于这样的前提，即体重减轻伴随着代谢和激素变化，这些变化有利于体重减轻的恢复，部分原因是瘦素的循环浓度降低，瘦素替代将使这些参数恢复到体重减轻前的水平。目的2检查胃旁路术和胃束带手术以及长期胃刺激在与下丘脑黑皮质素系统（ghrelin和PYY（3-36））相互作用的胃肠激素循环浓度中发生的变化。这些激素对测试餐的反应将被测量，并与饥饿和饱腹感相关。目的3的目的是检查多巴胺能和抗多巴胺能药物对下丘脑黑皮质素系统、体重和葡萄糖代谢的影响。本目标的第一部分描述了这些药物对食物摄入、体重和组成以及对大鼠下丘脑中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对减肥的生理反应，并有助于开发减肥和维持体重减轻的疗法。

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.