Insulin and Androgen Interactions in the Infertility of Obesity

描述（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。我们的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症、不孕症和肥胖背景下雄激素过多症的许多特征。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在肥胖症中表现出胰岛素抵抗，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，从而促进病理生理学。在目标 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系统的主要近端成分，包括 IR 和 IRS 亚型，并探讨胰岛素的急性作用。卵泡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 DIO 不孕症中的作用，并探讨介导卵巢中胰岛素作用（包括调节雄激素合成）的生理和病理生理相关信号传导途径。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孕。因此，这个假设将是 通过测量接受治疗的瘦小鼠垂体的胰岛素敏感性，直接在目标 2 中进行测试 与T，或在用T拮抗剂治疗的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）。将进行正常喂养动物的生殖功能和类固醇生成以及对 DIO 范式的反应的研究。从这些研究中获得的信息将有助于深入了解成年女性肥胖与生殖轴病理生理激活之间关联的胰岛素雄激素依赖性机制，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。 公共健康相关性：在本提案中，我们将尝试定义胰岛素和雄激素在肥胖引起的不孕症发展中的复杂相互作用。我们希望揭示代谢功能障碍（例如多囊卵巢综合症中常见的情况）女性不孕症发展的机制。

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.