HYPOTHALAMIC NEUROPEPTIDE PATHWAYS MEDIATING SYMPATHETIC RESPONSES TO LEPTIN

脂肪细胞产生的循环瘦素影响摄食行为， 通过其对中枢神经系统的影响来影响代谢过程。 最近的研究表明下丘脑神经肽Y（NPY）， 促肾上腺皮质激素释放因子（CRF）和黑皮质素在这些 流程.我们的初步数据表明，瘦素增加交感神经 神经活动（SNA）至肩胛内棕色脂肪组织（IBAT），肾上腺 腺（Adr）、肾和骨骼肌。瘦素影响摄食行为 通过其受体（OB-Rb）在下丘脑，这也是一个重要的 驱动交感神经系统的部位。然而， 哪种瘦素引发交感神经兴奋尚未确定。 当将促食欲肽NPY微量注射到IBAT SNA中时， 下丘脑室旁核（PVN），因此可以调节 交感兴奋性PVN神经元的活动。我们假设 这些神经元的兴奋由α黑素细胞刺激介导 激素（α-MSH），作用于MC 4-R受体最近已被 发现抑制进食行为，瘦素允许这种行为， 通过其已知的减少下丘脑NPY和NPY的作用而兴奋 在PVN中释放。我们还假设瘦素诱导交感神经兴奋 至少部分是由投射到PVN的含有CRF的神经元介导的。 脑干和脊髓三个神经控制实验室将 共同验证这些假设。马克博士的实验室将测试 离散化后循环瘦素对IBAT、Adr和肾SNA影响 下丘脑病变和局部微量注射肽（α-MSH 和NPY）和肽拮抗剂进入关键的下丘脑亚核。博士 Felder的实验室将测试NPY和α-MSH对单个PVN的影响， 神经元，以及它们在介导PVN神经元对瘦素的反应中的作用 输液约翰逊博士的实验室将使用免疫组织化学和 显微注射技术，以确定下降的CRF的作用- 含有PVN神经元介导对静脉注射瘦素的反应。 这些研究将提供重要的新的见解之间的联系， 瘦素，一种在脂肪组织中产生的体液信号，和 调节外周代谢功能的自主机制。

Circulating leptin produced by adipocytes influences feeding behavior and metabolic processes through its effects on the central nervous system. Recent studies have implicated hypothalamic neuropeptide Y (NPY), corticotrophin releasing factor (CRF) and the melanocortins in these processes. Our preliminary data indicate that leptin increases sympathetic nerve activity (SNA) to intrascapular brown adipose tissue (IBAT), adrenal gland (Adr), kidney, and skeletal muscle. Leptin affects feeding behavior via its receptors (OB-Rb) in the hypothalamus, which is also an important site driving the sympathetic nervous system. However, the mechanisms by which leptin initiates sympathetic excitation have not been determined. The Orexigenic peptide NPY inhibits IBAT SNA when microinjected into the paraventricular nucleus (PVN) of hypothalamus and thus may modulate the activity of sympathoexcitatory PVN neurons. We hypothesize that the excitation of these neurons is mediated by alpha melanocyte stimulating hormone (alpha-MSH), acting on the MC4-R receptors have recently been found to suppress feeding behavior, and that leptin permits this excitation by its known effect of reducing hypothalamic NPY and NPY release in PVN. We also hypothesize that leptin induced sympathoexcitation is mediated, at least in part, by CRF-containing PVN neurons projecting to brain stem and spinal cord. Three neural control laboratories will collaborate in testing these hypotheses. Dr. Mark's lab will test the effect of circulating leptin on IBAT, Adr and renal SNA after discrete hypothalamic lesions and regional microinjections of peptides (alpha-MSH and NPY) and peptide antagonists into critical hypothalamic subnuclei. Dr. Felder's lab will test the effects of NPY and alpha-MSH on single PVN neurons, and their role in mediating PVN neuronal responses to leptin infusion. Dr. Johnson's lab will use immunohistochemical and microinjection techniques to determine the role of descending CRF- containing PVN neurons in mediating the responses to intravenous leptin. These studies will provide important new insights into the link between leptin, a humoral signal generated in adipose tissue, and activation of autonomic mechanisms regulating peripheral metabolic function.