Involvement of Kisspeptin in Androgen-Induced Hypothalamic Endoplasmic Reticulum Stress and Its Rescuing Effect in PCOS Rats

Abstract

Background: 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. Methods: 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. Findings: 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 down-regulated 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. Interpretation: Our data has revealed an unexpected protective role of kisspeptin against ER stress and insulin resistance in the hypothalamus and provided a new treatment strategy targeting hypothalamic ER stress and insulin resistance with kisspeptin as a potential therapeutic agent. Funding Statement: National Basic Research Program of China, National Natural Science Foundation of China (2012CB944902, 2012CB944703, 2013CB967404, 2013CB967401, 2013CB967403, 81571403, 81471429) and State Key laboratory of Reproductive Medicine (SKLRM-K201805). Declaration of Interests: The authors have no conflicts of interest about this work. Ethics Approval Statement: The study was approved by the Ethics Committee of Tongji University and all patients gave informed consent. All procedures in this study were approved by the Animal Experimentation Ethics Committee of the Chinese University of Hong Kong, and the methods were used in accordance with the guidelines of the Chinses University of Hong Kong.