Role of Androgen Excess in Provoking Oxidative Stress in Females

多囊卵巢综合征（polycystic ovary syndrome，PCOS）是育龄妇女最常见的内分泌疾病。 PCOS表现为高雄激素血症，伴有慢性炎症，胰岛素抵抗， 抵抗和2型糖尿病（T2DM）。该提案中提出的证据表明，在妇女和 在小鼠中，过量的睾酮产生会产生炎症，从而改变脂肪生物学和胰岛素产生， 从而导致胰岛素抵抗、代谢综合征和T2DM。尽管有这些意见， 缺乏睾丸激素直接改变胰腺细胞胰岛素分泌的证据， 睾酮在破坏脂肪生物学，从而引起胰岛素抗性方面的作用尚未研究。目标 本申请的目的是证明女性中过量的睾酮易导致代谢紊乱， 通过作用于AR并引起胰腺细胞和脂肪细胞中的氧化应激， 本申请的具体目的是：通过使用AR基因敲除小鼠， （ARKO）在女性中，过量的睾酮激活AR细胞会引起胰岛素缺乏型糖尿病。 我们将测试这一假设，即过量的睾酮激活AR的细胞引起氧化应激。 我们将使用脂肪细胞AR基因敲除小鼠（FARKO）来确定，在雌性中， 脂肪细胞中AR的激活改变脂肪细胞因子的分泌并引发全身炎症， 胰岛素抵抗最后，我们将使用FARKO雌性小鼠和过量的脂肪细胞来测试这一假设。 睾酮对脂肪细胞中AR的作用引起氧化应激并破坏脂肪细胞因子的产生。 这些研究的成功完成将有助于将AR定义为高雄激素女性的靶点。这 将帮助该中心项目实现其支持改善妇女健康研究的目标。

The polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age in the U.S. The PCOS present with hyperandrogenism accompanied by chronic inflammation, insulin resistance and type 2 diabetes (T2DM). Evidence presented in this proposal suggests that in women and mice, excess testosterone production generates inflammation which alters fat biology and insulin production, thus contributing to insulin resistance, the metabolic syndrome and T2DM. Despite these observations, the evidence that testosterone directly alters insulin secretion from pancreatic ¿-cells is lacking and the role of testosterone in disrupting fat biology, thus provoking insulin resistance, has not been investigated. The goal of this application is to demonstrate that excess testosterone in females predisposes to the metabolic syndrome and T2DM by acting on AR and provoking oxidative stress in pancreatic ¿-cells and in fat-cells. The specific aims of this application are: To demonstrate, through use of the ¿-cell AR knockout mouse (¿ARKO) that in females, excess testosterone activation of AR in ¿-cells provokes insulin-deficient diabetes. We will test the hypothesis that excess testosterone activation of AR in ¿-cells provokes oxidative stress. We will use a fat-cell AR knockout mouse (FARKO) to establish that, in females, excess testosterone activation of AR in adipocytes alters adipocytokines secretion and provokes systemic inflammation and insulin resistance. Finally, we will test the hypothesis using FARKO female mice and adipocytes that excess testosterone action on AR in adipocytes provokes oxidative stress and disrupts adipocytokines production. Successful completion of these studies will help define the AR as a target in hyperandrogenic women. This will help this center program in achieving its goal of supporting research to improve women's health.