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: 8803856
• 负责人: Sheng Wu
• 金额: $ 24.9万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803856
• 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; 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.

概括 很难区分内脏肥胖，胰岛素抵抗和 生殖功能障碍的高狂力主义。我的学习目标是了解 肥胖相关信号影响生殖功能的机制。我们的实验室有 开发了女性不育症的饮食诱发肥胖（DIO）模型，该模型具有许多 PCOS的特征，不孕症和肥胖环境中的超雄激素。胰岛素和 雄激素可能会独立有效或在恶性循环中共同起作用。我们的 初步数据表明，虽然周围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。因此，胰岛素水平升高导致 生殖组织中的信号传导升高，这有助于病理生理。在AIM 1中， 胰岛素信号系统的主要近端成分，包括IR和IRS同工型 将在瘦肉和二氮小鼠的垂体和卵巢中进行研究以及胰岛素的急性作用 将被探索。 THECA细胞特异性胰岛素受体KO小鼠（Thirko）将用于研究 胰岛素信号传导在卵巢中的作用在正常发育和功能和介导 DIO中的不育症，以便在生理和病理生理上探测 信号通路介导卵巢中胰岛素的作用，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 不育。因此，该假设将通过测量胰岛素直接在AIM 2中进行检验 垂体在用T治疗的瘦小鼠或用T拮抗剂处理的DIO小鼠中的敏感性。 直接评估t对垂体和卵巢，促性腺营养和卵巢theca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）。 研究正常动物中生殖功能和类固醇发生的研究，并 将对DIO范式进行响应。从这些研究中获得的信息将 提供有关关联基础机制的胰岛素及其依赖机制的见解 肥胖与成年女性生殖轴的病理生理激活之间 以及PCOS中胰岛素，雄激素和肥胖症之间的复杂相互作用。