The Role of Energy Balance in Gonadotrope and Reproductive Function

项目摘要 多囊卵巢综合征（PCOS）是育龄妇女最常见的生育障碍。妇女 PCOS患者的促性腺激素、促黄体生成激素（LH）、雄激素、葡萄糖和炎症反应水平升高。 细胞因子PCOS女性和PCOS小鼠模型中LH和睾酮的伴随增加 与睾丸激素抑制神经内分泌轴的公认范式相反。机制 这一悖论背后的原因还未被探索。LH的翻译和分泌与生俱来依赖于能量 流程.因此，促性腺激素细胞代谢可以解释 雄激素（合成代谢类固醇）和LH在PCOS。本提案的总体目标是调查 促性腺激素葡萄糖代谢对正常和PCOS样条件下LH分泌和生育力的影响。的 这项建议的首要假设是，与PCOS相关的因素，包括葡萄糖，雄激素， 炎性细胞因子通过GLUT 1扰乱促性腺激素能量平衡，从而改变LH合成。 我们已经确定糖酵解是正常促性腺功能所需的代谢程序。 促性腺激素利用葡萄糖通过葡萄糖转运蛋白1（GLUT 1）支持LH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（GLUT 1）敲除对小鼠雌性生育力的影响。利用这个模型，我们 将破解雄激素如何增加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，增加促性腺激素对葡萄糖利用，以驱动LH分泌 GLUT 1。我们将评估在细胞系中沉默GLUT 1后雄激素对葡萄糖摄取的影响， 促性腺激素特异性GLUT1 KO小鼠，以确定促性腺激素GLUT1在PCOS中的作用。在目标2中，我们 阐明PCOS诱导的炎症对促性腺激素代谢和功能的作用。我们 假设慢性炎症直接调节促性腺激素LH分泌， PCOS的生殖功能障碍使用复杂的生物信息学方法，我们将确定 免疫表型特异性PCOS和评估免疫细胞的贡献PCOS病因使用 免疫缺陷转基因小鼠模型。总之，这些目标将1）概述促性腺激素能量的作用 生殖和PCOS的平衡，2）解释雄激素如何增加LH，3）识别特定的炎症 作为PCOS的潜在治疗靶点。

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.