Insulin and Androgen Interactions in the Infertility of Obesity

描述(由申请人提供)：很难区分内脏肥胖、胰岛素抵抗和高雄激素血症在生殖功能障碍中的不同作用。我的研究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，该模型具有多囊卵巢综合征、不孕症和肥胖背景下的高雄激素血症的许多特征。胰岛素和雄激素可能单独导致不孕症，也可能在恶性循环中共同作用。我们的初步数据表明，虽然外周储能组织在肥胖时表现出胰岛素抵抗，导致胰岛素水平升高，但生殖轴组织，特别是脑垂体和卵巢组织，仍然对胰岛素敏感。因此，胰岛素水平的升高导致生殖组织中信号的增加，这有助于病理生理。在目标1中，将研究胰岛素信号系统的主要近端成分，包括IR和IRS亚型在LEAN和DIO小鼠的垂体和卵巢中的作用，并探讨胰岛素的急性作用。将利用卵泡膜细胞特异性胰岛素受体KO小鼠(ThIRKO)研究卵巢胰岛素信号在DIO中的正常发育和功能以及在介导不孕症中的作用，并探讨卵巢中胰岛素调节雄激素合成等生理和病理生理相关的信号通路。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不育。因此，这一假设将是 通过测量瘦小鼠治疗后脑垂体的胰岛素敏感性，直接在AIM 2中进行测试 用T或用T拮抗剂处理的DIO小鼠。为了直接评估T对垂体和卵巢的影响，将产生促性腺激素和卵巢膜细胞特异性雄激素受体KO小鼠(分别为PitARKO和ThARKO)。将研究正常喂养动物的生殖功能和类固醇生成，以及对DIO范例的反应。从这些研究中获得的信息将为深入了解肥胖与成年女性生殖轴的病理生理激活之间的联系以及多囊卵巢综合征中胰岛素、雄激素和肥胖之间的复杂相互作用提供深入的胰岛素-雄激素依赖机制。 公共卫生相关性：在这项提案中，我们将尝试定义胰岛素和雄激素在肥胖引起的不孕不育发展过程中的复杂相互作用。我们希望揭示代谢紊乱妇女不孕不育的发病机制，就像在多囊卵巢综合征中经常观察到的那样。

DESCRIPTION (provided by applicant): 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 mechanisms 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 ofthe reproductive axis, particularly the pituitary and ovary, remain insulin sensitive. The elevated insulin levels, therefore, result in elevated signaling in reproductive tissues which contributes t 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. PUBLIC HEALTH RELEVANCE: In this proposal, we will attempt to define the complex interactions of insulin and androgens on the development of obesity induced infertility. We hope to uncover the mechanism that underlies the development of infertility in women with metabolic dysfunction such as what is frequently observed in PCOS.