NICHD Population Research Center (Project 5 supplement)

描述（申请人提供）：大脑处理和整合来自外周的代谢信号来调节体重和维持足够的燃料储备。神经内分泌生殖轴的活动受代谢激素控制，包括瘦素和胰岛素，它们反映代谢状态，并允许生殖活动。甘丙肽样肽（GALP）由作为瘦素调控靶点的弓形核神经元表达，在能量稳态和生殖的整合中发挥重要作用。我们已经证明GALP的中央管理刺激GnRH和LH分泌和增强男性性行为。我们还发现，胰岛素可诱导弓形核中GALP mRNA的表达，而实验诱导的糖尿病可抑制GALP mRNA的表达。糖尿病与促性腺激素分泌减少、不孕症和性功能障碍有关。这些观察结果表明，伴随糖尿病的性功能障碍可能部分归因于下丘脑GALP神经元活性的降低。以实验室大鼠为实验模型，我们提出实验来验证这一假设，并：1)探索胰岛素调节GALP神经元的分子途径；2)绘制GALP神经元在大脑中调节男性性行为的位置；3)识别GALP作用于生殖轴的受体。我们希望这一知识将有助于更好地理解GALP在大脑中的作用的基本生物学，为糖尿病性功能障碍的病因提供见解，并可能为其治疗提供开明和合理的途径。

DESCRIPTION (provided by applicant): The brain processes and integrates metabolic signals from the periphery to regulate body weight and maintain adequate fuel reserves. The activity of the neuroendocrine reproductive axis is gated by metabolic hormones, including leptin and insulin, which reflect metabolic status and whose presence is permissive to reproductive activity. Galanin-like peptide (GALP) is expressed by neurons in the arcuate nucleus that are targets for regulation by leptin and appear to play an important role in the integration of energy homeostasis and reproduction. We have demonstrated that central administration of GALP stimulates GnRH and LH secretion and enhances male sexual behavior. We have also shown that the expression of GALP mRNA in the arcuate nucleus is induced by insulin and suppressed by experimentally induced diabetes. Diabetes is associated with reduced gonadotropin secretion, infertility and dysfunctional sexual behavior. These observations suggest that the impairment of sexual function that accompanies diabetes may be attributable, in part, to reduced activity of GALP neurons in the hypothalamus. Using the laboratory rat as an experimental model, we propose experiments to test this hypothesis and: 1) to explore the molecular pathways by which insulin regulates GALP neurons; 2) to map the sites in the brain where GALP neurons act in the brain to regulate male sexual behavior; and 3) to identify the receptor(s) through which GALP acts to produce its effects on the reproductive axis. We hope this knowledge will lead to a better understanding of the basic biology of GALP's action in the brain, lend insight into the etiology of sexual dysfunction in diabetes, and perhaps provide an enlightened and rational path towards its treatment.