FETAL ANDROGEN INDUCES OVARIAN, LH AND B-CELL DEFECTS

胎儿雄激素导致卵巢、LH 和 B 细胞缺陷

• 批准号: 7929913
• 负责人: Jonathan Levin
• 金额: $ 24.31万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7929913
• 关键词: ATP sensitive potassium channel complex; Adolescence; Adrenal Glands; Adult; Anabolism; Androgenization; Androgens; Animal Model; Animals; Anovulation; Attenuated; Autonomic nervous system; B-Lymphocytes; Brain; Cardiovascular Diseases; Chronic; Defect; Deposition; Development; Disease; Endocrine; Environment; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Fasting; Fatty Acids; Fatty acid glycerol esters; Feedback; Female; Functional disorder; Funding; Gene Expression; Genes; Genetic; Glucose; Gonadotropins; Hepatic; Hormonal; Hyperandrogenism; Hyperglycemia; Hyperinsulinism; Hypothalamic structure; Infertility; Infusion procedures; Insulin; Insulin Resistance; Knockout Mice; Leptin; Link; Measures; Metabolic; Metabolic Diseases; Mus; Mutation; Neurons; Obesity; Ovarian; Ovariectomy; Ovary; Pathogenesis; Pattern; Peripheral; Phenotype; Potassium; Premenopause; Production; Progesterone Receptors; Program Development; Rattus; Refractory; Regulation; Relative (related person); Research Personnel; Resistance; Risk; Signal Transduction; Steroids; Symptoms; Syndrome; Testing; Tissues; Visceral; Wild Type Mouse; Woman; base; design; fetal; glucose production; in utero; insight; insulin sensitivity; insulin signaling; knockout gene; neuroregulation; novel; prenatal; programs; relating to nervous system; reproductive; reproductive axis; research study; sham surgery; subcutaneous; trait

Polycystic ovarian syndrome (PCOS) is a reproductive and metabolic disorder that occurs in 5-10% of premenopausal women, often producing infertility and increased risk of metabolic and cardiovascular disease. The combined evidence obtained by our SCOR investigators strongly supports our central hypothesis that PCOS has a genetic basis linked to excess androgen production, and that the androgen excess in the intrauterine environment programs the pathogenesis of the disorder. Our animal studies have provided further support for this hypothesis, showing that prenatal androgen exposure can program the development of PCOS-like phenotypic traits in rats and mice. The proposed experiments are designed to determine the mechanisms by which prenatal androgen exposure may program two of the most clinically important of these patho physio logical traits: hepatic insulin resistance and visceral adiposity. We have determined that prenatal androgenization (PNA) produces reproductive dysfunction in adulthood by programming resistance to several classic actions of estrogen (E2) in the brain. Estrogen was also found to induce expression of ATP sensitive potassium channel (KATp) subunit genes in hypothalamus; these channels have been shown to be critically important in the neural control of hepatic insulin sensitivity. Estrogen has also been shown to promote subcutaneous vs. visceral fat deposition by a hypothalamic action. We have therefore proposed the novel hypothesis that PNA programs development of hepatic insulin resistance and visceral adiposity by altering functional development of hypothalamic-autonomic control circuitries, rendering them resistant to regulation by E2, and hence depleted of KATp channels and compromised in their ability to regulate hepatic insulin sensitivity. To test this hypothesis, we will first determine if PNA programs reduced hypothalamic KATP channel expression and reduced hepatic responsiveness to hypothalamic KATP channel activation (Aim 1). We will then assess whether PNA programs impaired responsiveness of hypothalamic neurons to metabolic (Aim 2) and endocrine (Aim 3) signals that regulate hepatic insulin sensitivity. The ability of E2 to regulate hepatic insulin sensitivity and visceral adiposity by a hypothalamic action will then be assessed (Aim 4), using local infusions of E2 in the brain as well as a novel neuron-specific estrogen receptor-a knockout (NERKO) mouse to differentiate hypothalamic versus peripheral actions of E2. Finally, we will test whether PNA blocks E2 effects on these metabolic parameters in adulthood. These studies will provide important new information on mechanisms by which intrauterine androgen exposure programs metabolic pathophysiologies in adulthood, and may thus provide major new insights into the pathogenesis of metabolic dysfunction in PCOS women.

多囊卵巢综合征（PCOS）是一种生殖和代谢疾病，发生在5-10％ 绝经前妇女，通常会产生不育和代谢和心血管的风险增加 疾病。我们的SCOR调查人员获得的总证据强烈支持我们的中心 假设PCOS具有与过量雄激素产生有关的遗传基础，并且雄激素 宫内环境中的过量计划疾病的发病机理。我们的动物研究有 为这一假设提供了进一步的支持，表明产前雄激素暴露可以编程 大鼠和小鼠中PCOS样表型性状的发展。提出的实验设计为 确定产前雄激素暴露可能在临床上编程的两个机制 这些病情生理逻辑特征的重要性：肝胰岛素抵抗和内脏肥胖。 我们已经确定产前雄激素化（PNA）在成年期间产生生殖功能障碍 对大脑中雌激素（E2）的几种经典作用的编程耐药性。还发现雌激素 诱导下丘脑中ATP敏感钾通道（KATP）亚基基因的表达；这些 已证明通道在肝胰岛素敏感性的神经控制中至关重要。 还显示雌激素可以通过下丘脑促进皮下与内脏脂肪沉积 行动。因此，我们提出了一个新的假设，即PNA计划开发肝胰岛素 通过改变下丘脑自主控制的功能发展，耐药性和内脏肥胖 电路，使它们对E2的调节有抵抗力，因此耗尽了KATP通道和 他们调节肝胰岛素敏感性的能力受到妥协。为了检验这一假设，我们将首先 确定PNA程序是否降低了下丘脑KATP通道的表达并降低肝 对下丘脑KATP通道激活的反应（AIM 1）。然后，我们将评估PNA是否 计划障碍下丘脑神经元对代谢（AIM 2）和内分泌的反应性（AIM 3） 调节肝胰岛素敏感性的信号。 E2调节肝胰岛素敏感性和 然后，将使用下丘脑作用的内脏肥胖来评估（AIM 4），使用E2的局部输注 大脑以及一种新型神经元特异性雌激素受体-A敲除（Nerko）小鼠以区分 E2的下丘脑与外围作用。最后，我们将测试PNA是否块E2对这些影响 成年中的代谢参数。这些研究将提供有关机制的重要新信息 宫内雄激素暴露计划在成年中代谢病理生理，因此可能 提供有关PCOS女性代谢功能障碍的发病机理的主要新见解。