The Role of Energy Balance in Gonadotrope and Reproductive Function

项目总结 多囊卵巢综合征(PCOS)是育龄妇女最常见的生育障碍。女人 患有多囊卵巢综合征的患者促性腺激素、黄体生成素、雄激素、血糖和炎症 细胞因子。患有多囊卵巢综合征的女性和多囊卵巢综合征小鼠模型的黄体生成素和睾酮随之增加 反驳睾丸激素抑制神经内分泌轴的成熟范例。机制 在这一悖论的背后，很大程度上是未被探索的。黄体生成素的翻译和分泌是天生的能量依赖型 流程。因此，促性腺激素细胞代谢可能解释了 多囊卵巢综合征患者的雄激素(合成类固醇)和黄体生成素。这项提案的总体目标是调查 促性腺激素葡萄糖代谢对黄体生成素分泌和生育力的影响，在正常和类似多囊卵巢综合征的条件下。这个 这一建议的首要假设是与PCOS相关的因素，包括葡萄糖、雄激素和 炎性细胞因子通过GLUT1扰乱促性腺激素的能量平衡，从而改变促黄体生成素的合成。 我们已经确定糖酵解是正常促性腺激素功能所需的代谢程序。 促性腺激素通过葡萄糖转运蛋白1(GLUT1)利用葡萄糖支持黄体生成素的产生和分泌 排除葡萄糖转运蛋白家族的其他成员。在目标1中，我们将确定 促性腺激素特异性葡萄糖转运蛋白1(GLUT1)敲除小鼠的雌性生育能力。使用这个模型，我们 将破译雄激素如何促进促性腺激素葡萄糖代谢。我们假设雄激素 通过翻译前和翻译后调节促性腺激素对葡萄糖的利用来促进促黄体生成素的分泌 Glut1.我们将评估雄激素在沉默GLUT1细胞系和使用后对葡萄糖摄取的影响 促性腺激素特异性GLUT1 KO小鼠确定促性腺激素GLUT1在PCOS中的作用。在目标2中，我们将 阐明PCOS诱导的炎症对促性腺激素代谢和功能的影响。我们 假设慢性炎症直接调节促性腺激素黄体生成素的分泌，并有助于 多囊卵巢综合征患者的生殖功能障碍。使用复杂的生物信息学方法，我们将识别 PCOS特异性免疫表型及免疫细胞在PCOS病因学中的作用 免疫缺陷转基因小鼠模型。总之，这些目标将勾勒出促性腺激素能量的作用 生殖和多囊卵巢综合征的平衡，2)解释雄激素如何增加黄体生成素，3)识别特定的炎症 作为多囊卵巢综合征潜在治疗靶点的通路。

PROJECT SUMMARY Polycystic Ovary Syndrome (PCOS) is the most common fertility disorder in reproductive-aged women. Women with PCOS have elevated gonadotropin luteinizing hormone (LH), androgens, glucose, and inflammatory cytokines. Concomitant increases in LH and testosterone in both women with PCOS and mouse models of PCOS counter the well-established paradigm that testosterone suppresses the neuroendocrine axis. Mechanisms behind this paradox are largely unexplored. LH translation and secretion are innately energy-dependent processes. Therefore, gonadotrope cellular metabolism may explain the counterintuitive relationship between androgens (anabolic steroids) and LH in PCOS. The overall goal of this proposal is to investigate the impact of gonadotrope glucose metabolism on LH secretion and fertility in both normal and PCOS-like conditions. The overarching hypothesis of this proposal is that factors associated with PCOS, including glucose, androgens, and inflammatory cytokines, perturb gonadotrope energy balance through GLUT1 and therefore alter LH synthesis. We have determined that glycolysis is the metabolic program required for normal gonadotrope function. Gonadotropes utilize glucose to support LH production and secretion through Glucose transporter 1 (GLUT1) at the exclusion of other members of the glucose transporter family. In Aim 1, we will determine the effects of gonadotrope specific glucose transporter 1 (GLUT1) knock out on female fertility in mice. Using this model, we will decipher how androgens increase gonadotrope glucose metabolism. We hypothesize that androgens increase gonadotrope utilization of glucose to drive LH secretion by pre- and post- translational regulation of GLUT1. We will assess the impact of androgen on glucose uptake after silencing GLUT1 in cell lines and use gonadotrope specific GLUT1 KO mice to determine the role of gonadotrope GLUT1 in PCOS. In Aim 2, we will elucidate the contribution of PCOS-induced inflammation to gonadotrope metabolism and function. We hypothesize that chronic inflammation directly modulates gonadotrope LH secretion and contributes to reproductive dysfunction in PCOS. Using complex bioinformatic approaches, we will identify the immunophenotype specific to PCOS and assess the contribution of immune cells to PCOS etiology using immune deficient transgenic mouse models. Together, these Aims will 1) outline a role for gonadotrope energy balance in reproduction and PCOS, 2) explain how androgens increase LH, and 3) identify specific inflammatory pathways as potential therapeutic targets in PCOS.