Involvement of kisspeptin in androgen-induced hypothalamic endoplasmic reticulum stress and its rescuing effect in PCOS rats

• Published in: Biochimica et biophysica acta. Molecular basis of disease 2021-12, Vol.1867 (12), p.166242-166242, Article 166242
• Main Authors: Yuan, Chun, Huang, Wen Qing, Guo, Jing Hui, Liu, Xing Yan, Yang, Jian Zhi, Chen, Jun Jiang, Wu, Yong, Ruan, Ye Chun, Liu, Jia Yin, Cui, Yu Gui, Diao, Fei Yang, Chan, Hsiao Chang
• Format: Article
• Language: English
• Subjects: Androgen; Androgens - adverse effects; Animals; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Disease Models, Animal; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum - pathology; Endoplasmic reticulum stress; Endoplasmic Reticulum Stress - genetics; Female; Hypothalamus - metabolism; Hypothalamus - pathology; Insulin resistance; Insulin Resistance - genetics; Kisspeptin; Kisspeptins - blood; Kisspeptins - genetics; Neurons - metabolism; Neurons - pathology; Obesity - metabolism; Obesity - pathology; Polycystic ovary syndrome; Polycystic Ovary Syndrome - blood; Polycystic Ovary Syndrome - genetics; Polycystic Ovary Syndrome - pathology; Rats; Testosterone - blood; Unfolded protein response; Unfolded Protein Response - genetics
• ISSN: 0925-4439; 1879-260X
• DOI: 10.1016/j.bbadis.2021.166242

Endoplasmic reticulum (ER) stress, with adaptive unfolded protein response (UPR), is a key link between obesity, insulin resistance and type 2 diabetes, all of which are often present in the most common endocrine-metabolic disorder in women of reproductive age, polycystic ovary syndrome (PCOS), which is characterized with hyperandrogenism. However, the link between excess androgen and endoplasmic reticulum (ER) stress/insulin resistance in patients with polycystic ovary syndrome (PCOS) is unknown. An unexpected role of kisspeptin was reported in the regulation of UPR pathways and its involvement in the androgen-induced ER stress in hypothalamic neuronal cells. To evaluate the relationship of kisspeptin and ER stress, we detected kisspeptin and other factors in blood plasm of PCOS patients, rat models and hypothalamic neuronal cells. We detected higher testosterone and lower kisspeptin levels in the plasma of PCOS than that in non-PCOS women. We established a PCOS rat model by dihydrotestosterone (DHT) chronic exposure, and observed significantly downregulated kisspeptin expression and activated UPR pathways in PCOS rat hypothalamus compared to that in controls. Inhibition or knockdown of kisspeptin completely mimicked the enhancing effect of DHT on UPR pathways in a hypothalamic neuronal cell line, GT1–7. Kp10, the most potent peptide of kisspeptin, effectively reversed or suppressed the activated UPR pathways induced by DHT or thapsigargin, an ER stress activator, in GT1–7 cells, as well as in the hypothalamus in PCOS rats. Similarly, kisspeptin attenuated thapsigargin-induced Ca2+ response and the DHT- induced insulin resistance in GT1–7 cells. Collectively, the present study has revealed an unexpected protective role of kisspeptin against ER stress and insulin resistance in the hypothalamus and has provided a new treatment strategy targeting hypothalamic ER stress and insulin resistance with kisspeptin as a potential therapeutic agent. •Higher testosterone and lower Kisspeptin levels in PCOS women•Suppressed Kisspeptin expression and enhanced unfolded protein response (UPR) pathways in the hypothalamus of PCOS rats•Kisspeptin reverses the DHT-activated UPR pathways in GT1–7 cells.•Kisspeptin reverses UPR pathway markers expression in the hypothalamus of DHT-induced PCOS rats.