Department of Obstetrics and Gynecology, Medical Research Centre, Research Unit of Clinical Medicine, University of Oulu, Oulu University Hospital, Oulu, Finland; Research Unit of Extracellular Matrix and Hypoxia, Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland.
Department of Obstetrics and Gynecology, Medical Research Centre, Research Unit of Clinical Medicine, University of Oulu, Oulu University Hospital, Oulu, Finland.
Biochem Pharmacol. 2024 Nov;229:116522. doi: 10.1016/j.bcp.2024.116522. Epub 2024 Sep 6.
Polycystic ovary syndrome (PCOS) is a highly prevalent disorder in women that is commonly accompanied by metabolic syndrome. Activation of the hypoxia-inducible factor (HIF) pathway is known to alleviate metabolic defects. Hence, this study utilized a preclinical PCOS mouse model to investigate the effects of chemically induced HIF activation on the metabolic traits of PCOS. Prepubertal letrozole treatment was used to generate a PCOS mouse model in the C57Bl6/J strain, and PCOS mice were orally treated with vehicle or roxadustat for six weeks from age 12 weeks onwards to induce HIF activation. Although the PCOS mice showed impaired glucose tolerance, increased insulin resistance, elevated blood lipids, and reduced muscle glycogen content, there was no difference in histological evaluations of white adipose tissue (WAT) or liver or in organ weights. Roxadustat treatment resulted in significant improvement in glucose tolerance (27 % reduction in area under the curve (AUC) values, p < 0.0001), fasting glucose levels (4.59 ± 0.83 mmol/l vs 3.05 ± 0.62 mmol/l, p < 0.0001) and insulin resistance (46 % reduction in homeostasis model assessment-insulin resistance (HOMA-IR) values, 6.76 ± 3.72 vs 3.64 ± 2.44, p = 0.019) compared to vehicle-treated mice without altering the body weight. Gene expression analyses with real-time quantitative polymerase chain reaction (RT-qPCR) and RNA sequencing revealed significant differences in gene expression in the tissues of PCOS mice compared to control mice, whereas the transcriptomic effects of roxadustat were mainly transient. However, immunohistochemistry revealed increased uncoupling protein 1 (UCP1) expression in WAT, which may indicate WAT browning related to HIF pathway activation.
多囊卵巢综合征（PCOS）是一种在女性中普遍存在的疾病，常伴有代谢综合征。已知缺氧诱导因子（HIF）通路的激活可减轻代谢缺陷。因此，本研究利用临床前 PCOS 小鼠模型研究化学诱导的 HIF 激活对 PCOS 代谢特征的影响。使用预青春期来曲唑处理来生成 C57Bl6/J 品系的 PCOS 小鼠模型，并且从 12 周龄开始，用载体或罗沙司他对 PCOS 小鼠进行口服治疗，持续 6 周，以诱导 HIF 激活。尽管 PCOS 小鼠表现出葡萄糖耐量受损、胰岛素抵抗增加、血脂升高和肌肉糖原含量降低，但白色脂肪组织（WAT）或肝脏的组织学评估或器官重量没有差异。罗沙司他治疗导致葡萄糖耐量显著改善（曲线下面积（AUC）值降低 27%，p<0.0001），空腹血糖水平（4.59±0.83mmol/l 与 3.05±0.62mmol/l，p<0.0001）和胰岛素抵抗（稳态模型评估-胰岛素抵抗（HOMA-IR）值降低 46%，6.76±3.72 与 3.64±2.44，p=0.019）与载体处理的小鼠相比，而体重没有改变。实时定量聚合酶链反应（RT-qPCR）和 RNA 测序的基因表达分析显示，与对照小鼠相比，PCOS 小鼠组织中的基因表达存在显著差异，而罗沙司他的转录组效应主要是短暂的。然而，免疫组织化学显示 WAT 中解偶联蛋白 1（UCP1）表达增加，这可能表明与 HIF 通路激活相关的 WAT 褐变。
