Energy-Related Peptides and Reproductive Axis

描述（由申请人提供）：营养缺乏与生殖功能障碍有关，可导致功能性下丘脑慢性排卵（FHCA）。尽管这是不孕症的常见原因，但向大脑发出信号的确切代谢线索仍有待确定。我们的主要目的是调查最近发现的能量相关肽，如外周分泌的ghrelin和中枢分泌的agouti-related肽（AGRP），可能作为线索，调节促性腺激素释放激素（GnRH）脉冲发生器，起搏器的下丘脑-垂体-性腺（HPG）轴。由于这些肽是促食欲的，并且在禁食期间上调，我们的中心研究假设是，在正常动物中施用这些肽将模拟进食不足状态，并导致GnRH脉冲发生器的抑制。目的1和2将研究AGRP或ghrelin输注是否可以抑制脉冲式LH释放，这是GnRH脉冲活性的反映。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2种肽之间的协同作用。由于AGRP和ghrelin均激活下丘脑-垂体-肾上腺（HPA）轴，因此其他方案将记录功能性中枢通路（包括HPA）在介导这些能量相关肽对GnRH脉冲发生器的作用中的作用。在目标3和4中，我们将把我们的研究扩展到能量相关肽在2种改变GnRH/LH脉动的生理病理模型中的作用，一种引起食物限制，另一种引起心因性应激，并研究能量相关肽的直接或间接拮抗或瘦素（一种促性腺激素肽）的输注是否可以恢复正常的脉动活性。我们的研究将在恒河猴中进行，恒河猴是一种非人灵长类动物，能够很好地模拟人类生殖系统的生理学和病理生理学。总的来说，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，也可能是心因性应激相关的生殖功能障碍和不孕症的作用。

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.