NEUROPEPTIDE Y AND ITS ROLE IN CONGENITAL OBESITY

神经肽 Y 及其在先天性肥胖中的作用

基本信息

批准号：
3245553
负责人：
IAN L TAYLOR
金额：
$ 2.93万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-06-15 至 1993-06-30
项目状态：
已结题

项目摘要

When injected into the cerebral ventricular or paraventricular nucleus (PVN), Neuropeptide Y (NPY) is the most potent stimulant of food intake known. It also stimulates the release of corticotropin releasing hormone (CRH), ACTH and cortisol. This latter action is dose dependent and shared by the structurally related peptide, pancreatic polypeptide (PP). NPY nerves that influence the PVN arise from the Nucleus Tractus Solitarius in the dorsal vagal comples and the amygdala. Bilateral destruction of the amygdala results in anorexia and weight loss in experimental animals. We propose 1) to compare NPY contents and NPY mRNA levels in that amygdala and PVN of obese and lean rats, 2) examine NPY binding in the hippocampus and PVN of obese and lean rats and mice, 3) examine structure-function requirements fro binding to these regions of the brain, 4) crosslink and characterize these receptor populations in obese and lean animals, 5) contrast NPY's ability to stimulate the release of CRH in obese and lean animals. These studies will be performed in male and female rats. Adrenalectomy abolishes the ability of NPY to stimulate food intake suggesting a relationship between the NPY's ability to stimulate food intake and the HPA axis. Congenital obese rodents, particularly males, exhiit a hyperactive hypothalamic- pituitary-adrenal axis (HPA) and adrenalectomy reverse the obesity in congenitally obese rodents. We will determine the effects of adrenalectomy and steroid supplementation on NPY contents in the amygdala and PVN and NPY binding to the hippocampus and PVN in Sprague Dawley rats. Similar studies will be repeated in obese rats. In prior studies we have established that ob/ob mice fail to release PP in response to a meal, a characteristic thay share with Prader-Willi children. Treatment with bovine PP is the only other treatment, other than adrenalectomy, that reverse the obesity and diabetes seen in these animals . Using autoradiography will have identified novel PP receptor populations in the brain (NTS) and adrenal that may mediate these beneficial effects. We will contrast bbinding of PP to the NTS in bese and lean rats and mice. We will also characterize the PP receptor population in the Zona Fasiculata and determine if PP inhibits corticosterone release. NPY and PP are structurally related peptides that are capable of modifying feeding behaviors and/or the HPA axis. These studies will clarify how these structurally related brain-gut peptides interact to control body weight.

当注射到脑室或室旁核时 (PVN)、神经肽 Y (NPY) 是最有效的食物摄入兴奋剂已知。它还刺激促肾上腺皮质激素的释放激素 (CRH)、ACTH 和皮质醇。后一种作用是剂量依赖性的并由结构相关的肽、胰多肽共享（PP）。影响 PVN 的 NPY 神经来自束核背侧迷走神经复合体和杏仁核中的孤寂者。双边杏仁核的破坏会导致厌食症和体重减轻实验动物。我们建议1）比较NPY内容和NPY 肥胖和瘦大鼠杏仁核和 PVN 的 mRNA 水平，2) 检查肥胖和瘦大鼠和小鼠的海马和 PVN 中的 NPY 结合， 3) 检查与这些区域结合的结构功能要求大脑的，4）交联并表征这些受体群体在肥胖和瘦动物中，5) 对比 NPY 刺激肥胖和瘦动物体内 CRH 的释放。这些研究将在雄性和雌性大鼠中进行。肾上腺切除术消除了这种能力 NPY 刺激食物摄入表明两者之间存在关系 NPY 刺激食物摄入和 HPA 轴的能力。先天性肥胖的啮齿动物，尤其是雄性，表现出过度活跃的下丘脑垂体-肾上腺轴（HPA）和肾上腺切除术逆转了肥胖先天性肥胖的啮齿动物。我们将确定影响肾上腺切除术和补充类固醇对 NPY 含量的影响斯普拉格中杏仁核、PVN 和 NPY 与海马体和 PVN 结合道利鼠。类似的研究将在肥胖大鼠中重复进行。在之前的我们已经证实 ob/ob 小鼠在体内无法释放 PP 对膳食的反应，这是普瑞德-威利共有的一个特征孩子们。牛 PP 治疗是唯一的其他治疗方法，其他比肾上腺切除术更能逆转这些患者的肥胖和糖尿病动物。使用放射自显影术将鉴定出新的 PP 受体大脑（NTS）和肾上腺中的群体可能介导这些有益的影响。我们将首先对比 PP 的绑定与 NTS 以及瘦大鼠和小鼠。我们还将表征 PP 受体束状带中的种群并确定 PP 是否抑制皮质酮释放。 NPY 和 PP 是结构相关的肽能够改变进食行为和/或 HPA 轴。这些研究将阐明这些结构上相关的脑肠如何肽相互作用来控制体重。