Insulin and Androgen Interactions in the Infertility of Obesity

描述（由申请人提供）：内脏肥胖、胰岛素抵抗和高雄激素在生殖功能障碍中的各种作用很难区分。我的研究目标是了解肥胖相关信号影响生殖功能的机制。我们实验室建立了一种女性不孕症的饮食性肥胖（DIO）模型，该模型具有多囊卵巢综合征（PCOS）、不孕症和高雄激素症在肥胖背景下的许多特征。胰岛素和雄激素可能单独或共同导致不孕症，形成恶性循环。我们的初步数据表明，虽然肥胖患者的外周能量储存组织表现出胰岛素抵抗，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，胰岛素水平的升高导致生殖组织信号的升高，从而参与病理生理。在Aim 1中，胰岛素信号系统的主要近端组分，包括IR和IRS异构体，将在瘦肉小鼠和DIO小鼠的垂体和卵巢中进行研究，并探讨胰岛素的急性作用。我们将利用卵泡细胞特异性胰岛素受体KO小鼠（ThIRKO）来研究卵巢中胰岛素信号在DIO正常发育和功能中的作用，以及在介导不育中的作用，以探索胰岛素在卵巢中的作用的生理和病理生理相关信号通路，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和不孕症。因此，这个假设将是

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.