PROJECT 2 - METABOLIC CONTROL OF REPRODUCTION

复制的能源成本非常高。怀孕所需的能量估计为 160，000真实的，额外500-1000千卡/天用于哺乳。由于这一要求， 在饥荒时期，已经进化出抑制繁殖的机制。我们的目标是了解 整合的代谢在调节生育能力和如何异常代谢稳态，既 营养过剩或不足都可能导致不孕。脂肪衍生肽激素脂联素， 衰老相关蛋白SirT 1和PPARy受体都相互交叉调节胰岛素敏感性， 在各种组织中发挥多种生物效应。因此，这些蛋白质在控制GnRH中的作用 和促性腺激素基因的表达，合成，分泌和生育力在胰岛素抵抗产前 雄激素化小鼠将利用体内和体外方法的组合来解决。 在第一个具体目标中，我们将检验SirT 1和脂联素抑制中枢HPG的假设 轴在营养匮乏时期。这将使用组织特异性SirT 1敲除进行测试， 脑和垂体促性腺激素中的转基因物，以及脂联素缺失小鼠。在第二个具体目标中， 我们将测试高脂肪饮食增加下丘脑炎症信号的假设， 促性腺激素分泌失调，并且PPARy抑制炎性 使LH水平正常化。这将使用PPARv受体的组织特异性缺失进行测试， 促性腺激素或在整个脑中以鉴定PPARy作用的位点。在第三个具体目标中，我们将 检验产前雄激素化小鼠具有增加的组织炎症的假设， 会导致胰岛素抵抗我们将确定胰岛素抵抗的部位， 改善胰岛素抵抗挽救了这些小鼠的不育症。每个目标都将包含一系列体内 动物研究与一系列补充的体外实验配对，以阐明分子生物学 机制等

Reproduction is very energy expensive. The energy requirement for a pregnancy is estimated at 160,000 Real with an additional 500-1000 kcal/day for lactation. Because of this requirement, it is likely that mechanisms have evolved to suppress reproduction under periods of famine. Our goal is to understand the ntegration of metabolism in the regulation of fertility and how abnormalities in metabolic homeostasis, both over and under-nutrition, can lead to infertility. The adipose-derived peptide hormone adiponectin, the ongevity-associated protein SirT1, and the PPARy receptor all intersect to regulate insulin sensitivity and exert multiple biological effects in various tissues. Therefore, the role of these proteins in controlling GnRH and gonadotropin gene expression, synthesis, secretion, and fertility in the insulin-resistant prenatal androgenized mouse will be addressed utilizing a combined in vivo and in vitro approach. In the first specific aim, we will test the hypothesis that SirT1 and adiponectin suppress the central HPG axis during times of nutritional deprivation. This will be tested using tissue-specific SirT1 knockouts and transgenics in the brain and pituitary gonadotrope, and adiponectin null mice. In the second specific aim, we will test the hypothesis that a high fat diet increases inflammatory signaling in the hypothalamus and pituitary leading to dysregulation of gonadotropin secretion, and that PPARy suppresses inflammatory signaling to normalize LH levels. This will be tested using tissue-specific deletion of the PPARv receptor in gonadotropes or in the whole brain to identify the site of PPARy action. In the third specific aim, we will test the hypothesis that the prenatally androgenized mouse has increased tissue inflammation that contributes to the insulin resistance. We will determine the site of insulin resistance and will test whether improving insulin resistance rescues the infertility in these mice. Each aim will feature a series of in vivo animal studies paired with a complementary series of in vitro experiments to elucidate molecular mechanisms.