Li Sheng, Ying Zhixiong, Gentenaar Max, Rensen Patrick C N, Kooijman Sander, Visser Jenny A, Meijer Onno C, Kroon Jan
Department of Medicine, Division of Endocrinology, Leiden University Medical Center, 2333ZA Leiden, the Netherlands.
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, 2333ZA Leiden, the Netherlands.
J Endocr Soc. 2023 Dec 20;8(1):bvad162. doi: 10.1210/jendso/bvad162. eCollection 2023 Dec 1.
Polycystic ovary syndrome (PCOS) is a complex metabolic disorder associated with obesity, insulin resistance, and dyslipidemia. Hyperandrogenism is a major characteristic of PCOS. Increased androgen exposure is believed to deregulate metabolic processes in various tissues as part of the PCOS pathogenesis, predominantly through the androgen receptor (AR). Notably, various metabolic features in PCOS are similar to those observed after excess glucocorticoid exposure.
We hypothesized that glucocorticoid receptor (GR) signaling is involved in the metabolic symptoms of PCOS.
In a PCOS model of chronic dihydrotestosterone (DHT) exposure in female mice, we investigated whether GR signaling machinery was (de)regulated, and if treatment with a selective GR antagonist alleviated the metabolic symptoms.
We observed an upregulation of GR messenger RNA expression in the liver after DHT exposure. In white adipose tissues and liver we found that DHT upregulated , which encodes for the enzyme that converts inactive into active glucocorticoids. We found that preventive but not therapeutic administration of a GR antagonist alleviated DHT-induced hyperglycemia and restored glucose tolerance. We did not observe strong effects of GR antagonism in DHT-exposed mice on other features like total fat mass and lipid accumulation in various tissues.
We conclude that GR activation may play a role in glucose metabolism in DHT-exposed mice.
多囊卵巢综合征（PCOS）是一种与肥胖、胰岛素抵抗和血脂异常相关的复杂代谢紊乱疾病。高雄激素血症是PCOS的主要特征。雄激素暴露增加被认为是PCOS发病机制的一部分，主要通过雄激素受体（AR），使各种组织中的代谢过程失调。值得注意的是，PCOS中的各种代谢特征与过量糖皮质激素暴露后观察到的特征相似。
我们假设糖皮质激素受体（GR）信号传导参与PCOS的代谢症状。
在雌性小鼠慢性双氢睾酮（DHT）暴露的PCOS模型中，我们研究了GR信号传导机制是否被（去）调节，以及用选择性GR拮抗剂治疗是否能缓解代谢症状。
我们观察到DHT暴露后肝脏中GR信使核糖核酸表达上调。在白色脂肪组织和肝脏中，我们发现DHT上调了 ，其编码将无活性糖皮质激素转化为活性糖皮质激素的酶。我们发现预防性而非治疗性给予GR拮抗剂可缓解DHT诱导的高血糖并恢复葡萄糖耐量。我们未观察到GR拮抗作用对DHT暴露小鼠的其他特征（如总脂肪量和各种组织中的脂质积累）有显著影响。
我们得出结论，GR激活可能在DHT暴露小鼠的葡萄糖代谢中起作用。
