The Interaction of Neuroendocrine Repro. Function and Metabolic Signaling

在许多生理情况下，代谢信号，特别是与糖调节和脂质代谢相关的代谢信号，会影响生殖功能。控制代谢稳态和下丘脑（H）/垂体（P）/性腺（G）轴的网络非常复杂，反映了大量交叉反馈调节回路。在这个提议中，我们将对代谢信号系统的选定元素进行分子和生化解剖，以确定它们对HP功能的影响。因此，胰岛素、脂联素和PPARgamma信号传导都是主要代谢调节网络中的关键元件， 我们将检验一些与这些途径如何影响HP功能有关的假设。提出的方案是一个基础广泛的方法，涉及遗传，体内生理学和体外研究。具体而言，基于胰岛素受体（IR）的遗传缺失，很明显，大脑中IR的缺失会导致不育。我们自己的体外实验数据显示胰岛素对培养细胞中HP功能的实质性影响。我们将使用各种遗传学方法，包括基因敲除和转基因方法以及立体定位基因操作，以创建新的动物模型进行研究。还提出了永生化GnRH神经元细胞（GT 1 -7）和垂体细胞（L β T2）的体外研究。脂联素是一种脂肪源性因子， 对葡萄糖和脂质代谢有重要影响。转基因高脂联素血症小鼠不育，高脂联素血症大鼠LH分泌减少。这些发现将在遗传、生理和体外水平上进行，以了解这种脂肪细胞因子对生殖的影响。最后，刺激PPARgamma受体可以恢复PCOS妇女的生育能力，我们现在发现PPARgamma调节LbetaT 2细胞中的GnRH信号和LH释放。此外，我们有初步证据表明，TZD治疗PCOS妇女降低LH水平升高。总之，这种方法应该使我们能够解析出特定的代谢信号通路，以推断出它们对HP功能的单独和组合影响。这些研究将为代谢稳态和生殖功能之间的相互作用提供新的见解，使我们开始解开这些多方面的相互作用途径。这些结果也将提高我们对代谢性疾病如PCOS、2型糖尿病和肥胖症的生殖功能的理解，其中HP功能的异常已经得到了很好的描述。

There are a number of physiologic situations in which metabolic signals, particularly those related to glucoregulatory and lipid metabolism, impinge on reproductive function. The networks that control metabolic homeostasis and the hypothalamic (H)/pituitary (P)/gonadal (G) axis are highly complex, reflecting a large set of intersecting feedback regulatory circuits. In this proposal, we will undertake a molecular and biochemical dissection of selected elements of the metabolic signaling system to determine their impact on HP function. Thus, insulin, adiponectin, and PPARgamma signaling are all key elements in major metabolic regulatory networks, and we will test a number of hypotheses related to how these pathways affect HP function. The program proposed is a broad-based approach involving genetic, in vivo physiology, and in vitro studies. In specific, based on genetic deletion of insulin receptors (IR), it is clear that absence of IRs in the brain leads to infertility. Our own in vitro data show substantial effects of insulin on HP function in cultured cells. We will use a variety of genetic approaches, including knockout and transgenic methodology as well as stereotaxic gene manipulation to create novel animal models for investigation. In vitro studies in immortalized GnRH neuronal cells (GT1-7) and pituitary cells (LbetaT2) are also proposed. Adiponectin is an adipose-derived factor that has major effects on glucose and lipid metabolism. Transgenic hyperadiponectinemic mice are infertile and hyperadiponectinemic rats display decreased LH secretion. These findings will be pursued at genetic, physiologic, and in vitro levels to understand the effects of this adipocytokine on reproduction. Lastly, stimulation of the PPARgamma receptor can restore fertility in PCOS women, and we have now found that PPARgamma modulates GnRH signaling and LH release in LbetaT2 cells. In addition, we have initial evidence showing that TZD treatment of PCOS women lowers the elevated LH levels. Taken together, this approach should allow us to parse out specific metabolic signaling pathways to deduce their individual and combined effects on HP function. These studies should provide new insights into the interactions between metabolic homeostasis and reproductive function allowing us to begin unraveling these multi-faceted interacting pathways. The results will also improve our understanding of reproductive function in metabolic disorders such as PCOS, Type 2 diabetes, and obesity, in which abnormalities of HP function have been well described.