Androgen Excess Causes Adipogenic Dysfunction in PCOS Women

项目概要/摘要 多囊卵巢综合征（PCOS）是一种以雄激素为特征的复杂的女性内分泌疾病 月经不调和多囊卵巢。影响6-10%的育龄妇女，60-95%的 多囊卵巢综合征妇女有胰岛素抵抗，这是夸大了增加总和腹部脂肪沉积， 易患代谢综合征和糖尿病，是心血管疾病（CVD）的危险因素。的 值得关注的是，体重正常的PCOS女性中雄激素过多与优先选择性卵巢癌密切相关。 腹部脂肪沉积和腹内脂肪量增加与血清空腹呈正相关 胰岛素和脂质水平。此外，这些PCOS妇女的雄激素过多也伴随着更大的 皮下（SC）腹部脂肪中小脂肪细胞（脂肪细胞）的比例，其中脂肪通常 存储.因此，正常体重的PCOS妇女可能具有降低的SC脂肪安全储存的能力， 胖了当能量摄入超过该能力时，SC腹部脂肪细胞可能过度填充脂质并促进 在异常（异位）位置的过量脂质沉积，其中氧化应激增加是代谢的基础 功能障碍（即，脂毒性）。我们假设正常体重的PCOS妇女雄激素过多改变了SC 腹部脂肪形成，定义为脂肪干细胞发育成成熟脂肪细胞的能力， 这样做会损害新陈代谢功能。此外，这些雄激素的作用可能起源于遗传性的变化， 这些干细胞或其发育中的脂肪细胞的基因，而不影响基因的DNA序列 自身（即表观遗传）。在这次NCTRI项目IV更新中，我们将1）研究 与体重和年龄匹配的正常体重PCOS女性相比， 正常雄激素排卵妇女（对照组），2）确定雄激素在SC腹干中的作用 接受抗雄激素治疗的PCOS妇女的细胞功能障碍及其与代谢的关系 或安慰剂通过临床试验和3）确定关键的表观遗传变化，区分SC腹干 与体重和年龄相匹配的对照妇女相比，这些PCOS妇女的细胞。理解 雄激素在正常体重PCOS妇女SC腹部脂肪形成过程中的作用及其对 通过干细胞分化实现代谢功能， 包括干细胞疗法和药物干预在内的策略，可以改善代谢 功能，降低其对CVD的易感性。

PROJECT SUMMARY/ABSTRACT Polycystic ovary syndrome (PCOS) is a complex endocrine disorder of women characterized by androgen excess, menstrual irregularity and polycystic ovaries. Affecting 6-10% of reproductive-aged women, 60–95% of PCOS women have insulin resistance that is exaggerated by increased total and abdominal fat deposition, predisposing to metabolic syndrome and diabetes as risk factors for cardiovascular disease (CVD). Of concern, androgen excess in PCOS women who are normal-weight is closely linked with preferential abdominal fat deposition and increased intra-abdominal fat mass that is positively correlated with serum fasting insulin and lipid levels. Moreover, androgen excess in these PCOS women also is accompanied by a greater proportion of small adipocytes (fat cells) in subcutaneous (SC) abdominal adipose where fat is normally stored. Therefore, normal-weight PCOS women may have a reduced capacity of SC adipose to safely store fat. When energy intake exceeds that capacity, SC abdominal adipocytes may overfill with lipid and promote excess lipid deposition in abnormal (ectopic) locations, where increased oxidative stress underlies metabolic dysfunction (i.e., lipotoxicity). We hypothesize that androgen excess in normal-weight PCOS women alters SC abdominal adipogenesis, defined as the ability of adipose stem cells to develop into mature adipocytes and, in doing so, impairs metabolic function. Further, these androgen actions may originate from heritable changes in the genes of these stem cells or their developing adipocytes without affecting the DNA sequence of the genes themselves (i.e. epigenetic). In this NCTRI Project IV renewal, we will 1) examine molecular mechanisms of SC abdominal adipogenesis in normal-weight PCOS women compared to weight- and age-matched normoandrogenic ovulatory women (controls), 2) determine the role of androgen action in SC abdominal stem cell dysfunction and its relationship to metabolism in these PCOS women receiving the antiandrogen, flutamide or placebo through a clinical trial and 3) identify crucial epigenetic changes that distinguish SC abdominal stem cells in such PCOS women compared to those of weight- and age-matched control women. Understanding androgen action during SC abdominal adipogenesis in normal-weight PCOS women and its adverse effects on metabolic function through stem cell differentiation allows development of new and personalized clinical strategies, including stem cell therapies and pharmacological interventions, that could improve metabolic function in PCOS women and decrease their susceptibility to CVD.