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对生殖功能障碍的各种作用。我的研究目标是了解肥胖相关信号影响生殖功能的机制。我们的实验室已经开发了一种女性不孕症的饮食诱导肥胖（DIO）模型，该模型具有肥胖背景下PCOS，不孕症和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，虽然外周储能组织表现出胰岛素抵抗的肥胖，导致胰岛素水平升高，组织的生殖轴，特别是垂体和卵巢，保持胰岛素敏感性。因此，升高的胰岛素水平导致生殖组织中的信号升高，这有助于病理生理学。在目的1中，将在瘦小鼠和DIO小鼠的垂体和卵巢中研究胰岛素信号传导系统的主要近端组分，包括IR和IRS亚型，并探索胰岛素的急性效应。将使用膜细胞特异性胰岛素受体KO小鼠（ThIRKO）研究卵巢中胰岛素信号传导在正常发育和功能中的作用以及在介导DIO不孕症中的作用，并探索介导卵巢中胰岛素效应（包括调节雄激素合成）的生理学和病理生理学相关信号传导途径。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，这一假设将 在目标2中通过测量治疗的瘦小鼠垂体的胰岛素敏感性直接测试 或在用T拮抗剂处理的DIO小鼠中。为了直接评估T对垂体和卵巢的影响，将产生促性腺激素细胞和卵巢卵泡膜细胞特异性雄激素受体KO小鼠（分别为PitARKO和ThARKO）。将对正常喂养动物的生殖功能和类固醇生成以及对DIO范式的反应进行研究。从这些研究中获得的信息将提供深入了解胰岛素-雄激素依赖性机制之间的关联肥胖和生殖轴的病理生理激活成年女性，以及胰岛素，雄激素和肥胖PCOS之间的复杂的相互作用。 公共卫生相关性：在这个建议中，我们将试图确定胰岛素和雄激素在肥胖引起的不孕症的发展中的复杂相互作用。我们希望揭示代谢功能障碍女性不孕症发生的机制，如PCOS中经常观察到的机制。

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.