Insulin and Androgen Interactions in the Infertility of Obesity

肥胖不孕症中胰岛素和雄激素的相互作用

基本信息

批准号：
9114133
负责人：
Sheng Wu
金额：
$ 23.58万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9114133
关键词：
Ablation Acute Adult Amenorrhea Androgen Antagonists Androgen Receptor Androgens Animal Feed CYP17A1 gene Cells Cholesterol Complex Cyclic AMP Data Development Diet Estrogens Exhibits Feedback Female Female infertility Fertility Flutamide Functional disorder Goals Health Hyperandrogenism Hyperinsulinism Hypothalamic structure Infertility Insulin Insulin Receptor Insulin Resistance Insulin Signaling Pathway Knockout Mice Laboratories Low-Density Lipoproteins MAP Kinase Gene Measures Mediating Metabolic Modeling Mus Obesity Ovarian Ovarian Diseases Ovary Pathogenesis Peripheral Pituitary Gland Play Pregnenolone Protein Isoforms Receptor Signaling Role Signal Pathway Signal Transduction Steroid biosynthesis Steroids Syndrome System Testing Testosterone Tissues Up-Regulation Visceral Woman Work design in vivo Model insight insulin secretion insulin sensitivity insulin signaling mouse model reproductive reproductive axis reproductive function research study response synthetic enzyme theca cell therapy development

项目摘要

Summary It is difficult to differentiate the various roles of visceral adiposity, insulin resistance, and hyperandrogenism on reproductive dysfunction. The goals of my studies are to understand the mechanism by which obesity related signals impact reproductive function. Our laboratory has developed a diet induced obesity (DIO) model of female infertility that shares many of the features of PCOS, infertility and hyperandrogenism in the setting of obesity. Insulin and androgen may contribute to infertility independently or work together in a vicious cycle. Our preliminary data suggest that while peripheral energy storage tissues exhibit insulin resistance in obesity, resulting in elevated insulin levels, the tissues of the reproductive axis, particularly the pituitary and ovary, remain insulin sensitive. The elevated insulin levels, therefore, result in elevated signaling in reproductive tissues which contributes to the pathophysiology. In Aim 1, the major proximal components of the insulin signaling system including IR and IRS isoforms will be studied in the pituitary and ovary of lean and DIO mice and the acute effects of insulin will be explored. Theca cell-specific insulin receptor KO mice (ThIRKO) will be used to study the role for insulin signaling in the ovary in normal development and function and in mediating infertility in DIO and in order to probe the physiologically and pathophysiologically relevant signaling pathways mediating the effects of insulin in the ovary which include regulating androgen synthesis. Androgen is also elevated in our DIO model, which may also contribute to insulin resistance and infertility. Therefore, this hypothesis will be directly tested in Aim 2 by measuring the insulin sensitivity of the pituitary in lean mice treated with T, or in DIO mice treated with T antagonists. To directly assess the effects of T on the pituitary and ovary, gonadotroph and ovarian theca cell specific androgen receptor KO mice will be produced (PitARKO and ThARKO, respectively). Studies for reproductive functionality and steroidogenesis in normal fed animals, and for the response to the DIO paradigm will be conducted. Information gained from these studies will provide insight into the insulin-androgen dependent mechanisms underlying the association between obesity and the pathophysiological activation of the reproductive axis in adult women as well as the complex interactions among insulin, androgens and obesity in PCOS.

概括很难区分内脏肥胖、胰岛素抵抗和胰岛素抵抗的不同作用。高雄激素血症对生殖功能障碍的影响。我的学习目标是了解肥胖相关信号影响生殖功能的机制。我们实验室有开发了一种女性不孕症的饮食诱导肥胖（DIO）模型，该模型具有许多共同点肥胖背景下多囊卵巢综合征、不孕症和雄激素过多症的特征。胰岛素和雄激素可能单独导致不孕，也可能共同作用形成恶性循环。我们的初步数据表明，虽然外周能量储存组织表现出胰岛素抵抗在肥胖中，导致胰岛素水平升高，生殖轴组织，特别是垂体和卵巢仍然对胰岛素敏感。因此，胰岛素水平升高会导致生殖组织中的信号传导增强，有助于病理生理学。在目标 1 中，胰岛素信号系统的主要近端成分，包括 IR 和 IRS 亚型将在瘦小鼠和 DIO 小鼠的垂体和卵巢中研究胰岛素的急性作用将被探索。膜细胞特异性胰岛素受体 KO 小鼠 (ThIRKO) 将用于研究卵巢中胰岛素信号传导在正常发育和功能以及介导中的作用 DIO 中的不孕症并探讨其生理学和病理生理学相关性介导卵巢中胰岛素作用的信号通路，包括调节雄激素合成。在我们的 DIO 模型中雄激素也升高，这也可能导致胰岛素抵抗和不孕症。因此，该假设将在目标 2 中通过测量胰岛素直接进行检验用 T 治疗的瘦小鼠或用 T 拮抗剂治疗的 DIO 小鼠的垂体敏感性。直接评估 T 对垂体和卵巢、促性腺激素和卵巢卵泡膜的影响将产生细胞特异性雄激素受体 KO 小鼠（分别为 PitARKO 和 ThARKO）。正常喂养动物的生殖功能和类固醇生成的研究，以及将进行对DIO范式的响应。从这些研究中获得的信息将深入了解该关联背后的胰岛素雄激素依赖性机制肥胖与成年女性生殖轴的病理生理激活之间的关系以及多囊卵巢综合征中胰岛素、雄激素和肥胖之间复杂的相互作用。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

An Improved Time- and Labor- Efficient Protocol for Mouse Primary Hepatocyte Isolation.

DOI：
10.3791/61812
发表时间：
2021-10-25
期刊：
JOVE-JOURNAL OF VISUALIZED EXPERIMENTS
影响因子：
1.2
作者：
Feng, Mingxiao;Divall, Sara;Wu, Sheng
通讯作者：
Wu, Sheng

Gonadotrope androgen receptor mediates pituitary responsiveness to hormones and androgen-induced subfertility.

促性腺激素雄激素受体介导垂体对激素和雄激素引起的生育力低下的反应。

DOI：
10.1172/jci.insight.127817
发表时间：
2019
期刊：
JCI insight
影响因子：
8
作者：
Wang,Zhiqiang;Feng,Mingxiao;Awe,Olubusayo;Ma,Yaping;Shen,Mingjie;Xue,Ping;Ahima,Rexford;Wolfe,Andrew;Segars,James;Wu,Sheng
通讯作者：
Wu,Sheng

Estrogen receptor-β in the gonadotropin-releasing hormone neuron.