Energy-Related Peptides and Reproductive Axis

描述(申请人提供)：营养缺乏与生殖功能障碍有关，并可导致功能性下丘脑慢性排卵(FHCA)。尽管这是不孕不育的常见原因，但向大脑发出信号的确切代谢线索仍有待确定。我们的主要目的是研究最近发现的能量相关多肽，如外周分泌的Ghrelin和中枢分泌的刺参相关肽(AGRP)是否可以作为调节促性腺激素释放激素(GnRH)脉冲发生器的线索，促性腺激素释放激素(GnRH)脉冲发生器是下丘脑-垂体-性腺轴的起搏器。由于这些多肽会产生食欲，并在禁食期间上调，我们的中心研究假设是，在正常动物体内服用这些多肽将模拟摄食不足的状态，并导致GnRH脉冲发生器的抑制。AIMS 1和2将研究AGRP或Ghrelin输注是否可以抑制反映GnRH脉冲活性的搏动性黄体生成素释放。由于AGRP与神经肽Y(NPY)共同位于弓状神经元中，我们还将研究这两种多肽之间的协同作用。由于AGRP和Ghrelin都激活下丘脑-垂体-肾上腺(HPA)轴，其他方案将记录包括HPA在内的功能中枢通路在这些能量相关肽对GnRH脉冲发生器的作用中的中介作用。在目标3和4中，我们将把我们的研究扩展到两个改变GnRH/LH脉动性的生理病理模型中，一个引起食物限制，另一个引起心理应激，并研究直接或间接拮抗能量相关肽或注入瘦素(一种厌氧生成肽)是否可以恢复正常的脉搏活动。我们的研究将在恒河猴身上进行，这是一种非人类灵长类动物，很好地模拟了人类生殖系统的生理学和生理病理学。总体而言，我们的数据将提供新的信息，支持新的食欲肽在营养相关的、可能也与心理应激相关的生殖功能障碍和不孕不育中的作用。

DESCRIPTION (provided by applicant): Nutritional deprivation is associated with reproductive dysfunction and can lead to functional hypothalamic chronic an ovulation (FHCA). Even though this is a frequent cause of infertility, the exact metabolic clues that signal the brain remain to be determined. Our main objective is to investigate whether recently discovered energy-related peptides, such as the peripherally-secreted ghrelin and the centrally-secreted agouti-related peptide (AGRP), may function as clues that modulate the gonadotropin-releasing hormone (GnRH) pulse generator, the pacemaker for the hypothalamic-pituitary-gonadal (HPG) axis. Since these peptides are orexigenic and are upregulated during fasting, our central research hypothesis is that administration of these peptides in a normal animal will mimic the under-fed state and result in the inhibition of the GnRH pulse generator. Aims 1 and 2 will investigate whether AGRP or ghrelin infusion can inhibit pulsatile LH release, a reflection of GnRH pulse activity. Because AGRP is co-located with neuropeptide Y (NPY) in arcuate neurons, we will also investigate synergy between these 2 peptides. Since both AGRP and ghrelin activate the hypothalamic-pituitary-adrenal (HPA) axis, additional protocols will document the role of functional central pathways, including that of HPA, in mediating the action of these energy-related peptides on the GnRH pulse generator. In aims 3 and 4, we will extend our studies to the role of energy-related peptides in 2 physiopathological models which modify GnRH/LH pulsatility, one evoking food restriction, the other a psychogenic stress, and investigate whether direct or indirect antagonism of energy-related peptides or an infusion of leptin, an anorexigenic peptide, can restore normal pulsatile activity. Our studies will be performed in the rhesus monkey, a non-human primate which mimics well the physiology and physiopathology of the human reproductive system. Overall, our data will provide novel information in support of a role of new orexigenic peptides in nutrition-related and perhaps also psychogenic stress-related reproductive dysfunction and infertility.