Abstract：
Excess levels of circulating androgens during prenatal or peripubertal development are an important cause of polycystic ovary syndrome (PCOS), with the brain being a key target. Approximately half of the women diagnosed with PCOS also experience metabolic syndrome; common features including obesity, insulin resistance and hyperinsulinemia. Although a large amount of clinical and preclinical evidence has confirmed this relationship between androgens and the reproductive and metabolic features of PCOS, the mechanisms by which androgens cause this dysregulation are unknown. Neuron-specific androgen receptor knockout alleviates some PCOS-like features in a peripubertal dihydrotestosterone (DHT) mouse model, but the specific neuronal populations mediating these effects are undefined. A candidate population is the agouti-related peptide (AgRP)-expressing neurons, which are important for both reproductive and metabolic function. We used a well-characterised peripubertal androgenized mouse model and Cre-loxP transgenics to investigate whether deleting androgen receptors specifically from AgRP neurons can alleviate the induced reproductive and metabolic dysregulation. Androgen receptors were co-expressed in 66% of AgRP neurons in control mice, but only in <2% of AgRP neurons in knockout mice. The number of AgRP neurons was not altered by the treatments. Only 20% of androgen receptor knockout mice showed rescue of DHT-induced androgen-induced anovulation and acyclicity. Furthermore, androgen receptor knockout did not rescue metabolic dysfunction (body weight, adiposity or glucose and insulin tolerance). While we cannot rule out developmental compensation in our model, these results suggest peripubertal androgen excess does not markedly influence Agrp expression and does not dysregulate reproductive and metabolic function through direct actions of androgens onto AgRP neurons.
摘要：
在产前或青春期发育期间循环雄激素水平过高是多囊卵巢综合征（PCOS）的重要原因，大脑是关键目标.大约一半被诊断患有PCOS的女性也会经历代谢综合征;常见特征包括肥胖，胰岛素抵抗和高胰岛素血症。尽管大量的临床和临床前证据证实了雄激素与PCOS的生殖和代谢特征之间的关系，雄激素导致这种失调的机制尚不清楚。神经元特异性雄激素受体敲除减轻青春期周二氢睾酮（DHT）小鼠模型中的一些PCOS样特征，但是介导这些作用的特定神经元群体是不确定的。候选群体是agouti相关肽（AgRP）表达神经元，这对生殖和代谢功能都很重要。我们使用了特征良好的青春期雄激素化小鼠模型和Cre-loxP转基因技术来研究从AgRP神经元特异性删除雄激素受体是否可以减轻诱导的生殖和代谢失调。雄激素受体在对照小鼠中66％的AgRP神经元中共表达，但仅在敲除小鼠中<2％的AgRP神经元中。AgRP神经元的数量没有被处理改变。只有20％的雄激素受体敲除小鼠显示出DHT诱导的雄激素诱导的无排卵和无周期。此外，雄激素受体敲除并不能挽救代谢功能障碍(体重，肥胖或葡萄糖和胰岛素耐量)。虽然我们不能排除我们模型中的发育补偿，这些结果表明，青春期雄激素过量不会显着影响Agrp的表达，也不会通过雄激素对AgRP神经元的直接作用来调节生殖和代谢功能。
