NEUROPEPTIDE Y AND ITS ROLE IN CONGENITAL OBESITY

当注射到脑室或室旁核时 脑室旁核(PVN)、神经肽Y(NPY)是食物摄入量最强的刺激物 为人所知。它还能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。 并由结构相关的多肽-胰多肽所共有 (PP)。影响下丘脑室旁核的NPY神经起源于中缝大核 迷走神经背侧复合体和杏仁核中的孤立性。双边 杏仁核的破坏会导致食欲减退和体重减轻 实验动物。我们建议1)比较NPY含量和NPY 肥胖和瘦大鼠杏仁核和下丘脑室旁核基因表达水平2)检测 肥胖和消瘦大鼠和小鼠海马区和下丘脑室旁核中NPY的结合 3)检查与这些区域结合的结构-功能要求 4)对这些受体群体进行交联化和表征 在肥胖和瘦肉动物中，对比NPY刺激 CRH在肥胖和瘦肉动物体内的释放。这些研究将是 在雄性和雌性大鼠身上进行。肾上腺切除术取消能力 NPY刺激食物摄取的作用表明 NPY刺激食物摄取和HPA轴的能力。先天 肥胖的啮齿动物，尤其是雄性，表现出下丘脑的过度活跃- 垂体-肾上腺轴(HPA)和肾上腺切除术逆转肥胖 先天肥胖的啮齿动物。我们将确定 肾上腺切除和补充类固醇对大鼠脑内神经肽Y含量的影响 大鼠杏仁核、室旁核和神经肽Y与海马和室旁核的结合 道利鼠。类似的研究将在肥胖大鼠身上重复进行。在之前 我们已经证实ob/ob小鼠在体内不能释放PP 对一顿饭的反应，这是他与Prader-Willi分享的特色 孩子们。用牛PP治疗是唯一的其他治疗方法，其他 比肾上腺切除更能逆转肥胖和糖尿病 动物。利用放射自显影将识别出新的PP受体 大脑(NTS)和肾上腺中可能介导这些变化的群体 有益的影响。我们将在BESE中对比PP和NTS的结合 瘦小的老鼠和老鼠。我们还将描述PP受体的特性 并确定PP是否具有抑制作用 皮质酮释放。NPY和PP是结构上相关的多肽 其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大脑-肠道 多肽相互作用以控制体重。

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.