PROJECT 2 - METABOLIC CONTROL OF REPRODUCTION

项目 2 - 生殖代谢控制

• 批准号: 7683482
• 负责人: jerrold Michael OLEFSKY
• 金额: $ 39.43万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7683482
• 关键词: Address; Adipose tissue; Affect; Age; Amenorrhea; Androgens; Animals; Anovulation; Anterior Pituitary Gland; Atherosclerosis; Biological; Brain; Caloric Restriction; Cell model; Clinical; Contraceptive methods; Diet; Dyslipidemias; Endocrine System Diseases; Exposure to; Famines; Fatty acid glycerol esters; Female; Fertility; Gene Expression; Genetic; Goals; Gonadotropins; Hirsutism; Homeostasis; Hypertension; Hypothalamic structure; Impairment; In Vitro; Infertility; Infiltration; Inflammation; Inflammatory; Insulin Resistance; Knock-out; Knockout Mice; Lactation; Lead; Longevity; Measures; Medicine; Metabolic; Metabolic Control; Metabolism; Modeling; Molecular; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Oligomenorrhea; Ovarian Cysts; Ovary; Peroxisome Proliferator-Activated Receptors; Physiological; Pituitary Gland; Polycystic Ovary Syndrome; Pregnancy; Proteins; Regulation; Reproduction; Research Project Grants; Risk; Role; Science; Series; Signal Transduction; Site; Testing; Time; Tissues; Transgenic Mice; Transgenic Organisms; Woman; adiponectin; deprivation; improved; in utero; in vivo; inflammatory marker; insulin sensitivity; macrophage; mature animal; metabolic abnormality assessment; mouse model; nutrition; overexpression; peptide hormone; prenatal; prevent; receptor; reproductive; reproductive function; reproductive hormone; research study; response

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.

繁殖是非常昂贵的能源。怀孕所需的能量估计为 16万雷亚尔，每天额外增加500-1000大卡的哺乳费用。由于这一要求，很可能 在饥荒时期，已经进化出了抑制生殖的机制。我们的目标是了解 代谢在生育调节中的整合以及代谢稳态的异常，两者都 营养过剩和营养不足会导致不孕不育。脂肪衍生多肽荷尔蒙脂联素， 长寿相关蛋白SirT1和PPARy受体都相交，调节胰岛素敏感性和 在各种组织中发挥多种生物效应。因此，这些蛋白在控制GnRH中的作用 胰岛素抵抗围产儿促性腺激素基因表达、合成、分泌和生育 雄激素小鼠将采用体内和体外相结合的方法进行治疗。 在第一个特定目标中，我们将检验SirT1和脂联素抑制中枢HPG的假设 在营养匮乏的时候。这将使用组织特异性SirT1基因敲除和 大脑和脑下垂体促性腺激素的转基因，以及脂联素缺失的小鼠。在第二个具体目标中， 我们将检验这一假设，即高脂肪饮食增加了下丘脑和 垂体导致促性腺激素分泌失调，PPARy抑制炎症 发出促黄体生成素水平正常化的信号。这将通过组织特异性删除PPARv受体来进行测试 促性腺激素或在整个大脑中识别PPARy的作用部位。在第三个具体目标中，我们将 验证这样一种假设，即产前雄激素生成的小鼠增加了组织炎症， 会导致胰岛素抵抗。我们将确定胰岛素抵抗的部位，并将测试 改善胰岛素抵抗可以挽救这些小鼠的不孕症。每个目标都将以一系列体内试验为特色 动物实验与一系列补充的体外实验相结合，以阐明分子 机制。