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

• 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
• 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

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.

总结 很难区分内脏肥胖、胰岛素抵抗和 高雄激素血症对生殖功能障碍的影响我研究的目标是了解 肥胖相关信号影响生殖功能的机制。本实验室 开发了一种女性不孕症的饮食诱导肥胖（DIO）模型， 肥胖背景下多囊卵巢综合征、不孕症和高雄激素血症的特征。胰岛素和 雄激素可能单独导致不育，也可能在恶性循环中共同起作用。我们 初步数据表明，虽然外周储能组织表现出胰岛素抵抗， 在肥胖症中，导致胰岛素水平升高，生殖轴的组织，特别是 垂体和卵巢保持胰岛素敏感性。因此，胰岛素水平升高导致 生殖组织中的信号升高，这有助于病理生理学。在目标1中， 胰岛素信号系统的主要近端组分，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。将使用膜细胞特异性胰岛素受体KO小鼠（ThIRKO）来研究胰岛素受体的表达。 胰岛素信号在卵巢正常发育和功能中的作用， 不孕症的DIO，以探讨生理和病理生理相关的 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， 不孕因此，将在目标2中通过测量胰岛素水平直接检验该假设。 用T处理的瘦小鼠或用T拮抗剂处理的DIO小鼠中垂体的敏感性。 直接评估T对垂体和卵巢、促性腺激素细胞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研究，以及 将对DIO模式进行响应。从这些研究中获得的信息将 提供了深入了解胰岛素-雄激素依赖性机制的基础协会 肥胖与成年女性生殖轴的病理生理激活之间的关系 以及PCOS中胰岛素、雄激素和肥胖之间复杂的相互作用。

项目成果

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.

促性腺激素释放激素神经元中的雌激素受体-β。

• DOI: 10.1055/s-0031-1299594
• 发表时间: 2012-01
• 期刊: Seminars in reproductive medicine
• 影响因子: 2.7

Lower FSH With Normal Fertility in Male Mice Lacking Gonadotroph Kisspeptin Receptor.

• DOI: 10.3389/fphys.2022.868593
• 发表时间: 2022
• 期刊: Frontiers in physiology
• 影响因子: 4

A Hyperandrogenic Mouse Model to Study Polycystic Ovary Syndrome.

用于研究多囊卵巢综合症的高雄激素小鼠模型。

• DOI: 10.3791/58379
• 发表时间: 2018
• 期刊: Journal of visualized experiments : JoVE
• 作者: Xue,Ping;Wang,Zhiqiang;Fu,Xiaomin;Wang,Junjiang;Punchhi,Gopika;Wolfe,Andrew;Wu,Sheng
• 通讯作者: Wu,Sheng