2. Academic Validation
  3. Roxadustat alleviates metabolic traits in letrozole-induced PCOS mice

Roxadustat alleviates metabolic traits in letrozole-induced PCOS mice

  • Biochem Pharmacol. 2024 Nov:229:116522. doi: 10.1016/j.bcp.2024.116522.
Nikke Virtanen 1,  Ulla Saarela 2,  Mikko Karpale 3,  Riikka K Arffman 2,  Kari A Mäkelä 4,  Karl-Heinz Herzig 5,  Peppi Koivunen 3,  Terhi Piltonen 6
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Obstetrics and Gynecology, Medical Research Centre, Research Unit of Clinical Medicine, University of Oulu, Oulu University Hospital, Oulu, Finland.
  • 3 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.
  • 4 Research Unit of Biomedicine and Internal Medicine, Biocenter Oulu, Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland.
  • 5 Research Unit of Biomedicine and Internal Medicine, Biocenter Oulu, Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland; Department of Gastroenterology and Metabolism, Poznan University of Medical Sciences, Poznan, Poland.
  • 6 Department of Obstetrics and Gynecology, Medical Research Centre, Research Unit of Clinical Medicine, University of Oulu, Oulu University Hospital, Oulu, Finland. Electronic address: terhi.piltonen@oulu.fi.
PMID: 39245394 DOI: 10.1016/j.bcp.2024.116522
Abstract

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.

Keywords

HIF prolyl 4-hydroxylase; Letrozole; Metabolism; PCOS; Prepubertal; Roxadustat.

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