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和 通过对中枢神经系统的影响来进行代谢过程。 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)及其黑素皮质素 流程。我们的初步数据显示，瘦素增加了交感神经 肾上腺囊内棕色脂肪组织的神经活动(SNA) 腺体(ADR)、肾脏和骨骼肌。瘦素影响进食行为 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站点。然而，这些机制通过 哪些瘦素能引起交感神经兴奋尚不清楚。 显微注射Orexigen多肽NPY抑制IBAT SNA 下丘脑室旁核(PVN)可能调节 交感兴奋性下丘脑室旁核神经元的活动。我们假设 这些神经元的兴奋是由α-黑素细胞刺激介导的 作用于MC4-R受体的激素(α-MSH)最近被 发现可以抑制摄食行为，而瘦素允许这样做 已知的降低下丘脑神经肽Y和神经肽Y的兴奋作用 在PVN中释放。我们还假设瘦素引起交感神经兴奋。 至少部分地由含有CRF的PVN神经元投射到 脑干和脊髓。三个神经控制实验室将 合作检验这些假说。马克博士的实验室将测试 循环瘦素对离散后IBAT、ADR及肾脏SNA的影响 下丘脑损害和局部注射多肽(α-MSH) 和NPY)和多肽拮抗剂进入关键的下丘脑亚核。Dr。 费尔德的实验室将测试NPY和α-MSH对单个PVN的影响 神经元及其在介导PVN神经元对瘦素反应中的作用 输液。约翰逊博士的实验室将使用免疫组织化学和 微量注射技术确定CRF下行的作用- 含PVN神经元在介导静脉注射瘦素反应中的作用。 这些研究将提供重要的新见解，揭示 瘦素，一种在脂肪组织中产生的体液信号，并激活 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.