Connolly Alexandre, Leblanc Samuel, Baillargeon Jean-Patrice
Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, 3001 12e Avenue Nord, Université de Sherbrooke, Sherbrooke, QC, Canada J1H 5N4.
Division of Endocrinology, Department of Medicine, Faculty of Medicine and Health Sciences, 3001 12e Avenue Nord, Université de Sherbrooke, Sherbrooke, QC, Canada J1H 5N4.
Int J Endocrinol. 2018 Jun 3;2018:4315413. doi: 10.1155/2018/4315413. eCollection 2018.
Polycystic ovary syndrome (PCOS) is a common and significant condition associated with hyperandrogenism, infertility, low quality of life, and metabolic comorbidities. One possible explanation of PCOS development is cellular dysfunction induced by nonesterified fatty acids (NEFAs), that is, lipotoxicity, which could explain both the hyperandrogenemia and insulin resistance that characterize women with PCOS. The literature suggests that androgen biosynthesis may be induced by overexposure of androgen-secreting tissues to NEFA and/or defective NEFA metabolism, leading to lipotoxic effects. Indeed, lipotoxicity could trigger androgenic hyperresponsiveness to insulin, LH, and ACTH. In most PCOS women, lipotoxicity also causes insulin resistance, inducing compensatory hyperinsulinemia, and may thus further increase hyperandrogenemia. Many approaches aimed at insulin sensitization also reduce lipotoxicity and have been shown to treat PCOS hyperandrogenemia. Furthermore, our group and others found that angiotensin II type 2 receptor (AT2R) activation is able to improve lipotoxicity. We provided evidence, using C21/M24, that AT2R activation improves adipocytes' size and insulin sensitivity in an insulin-resistant rat model, as well as androgen levels in a PCOS obese rat model. Taken together, these findings point toward the important role of lipotoxicity in PCOS development and of the RAS system as a new target for the treatment of PCOS.
多囊卵巢综合征（PCOS）是一种常见且严重的疾病，与高雄激素血症、不孕、生活质量低下及代谢合并症相关。PCOS发生的一种可能解释是非酯化脂肪酸（NEFAs）诱导的细胞功能障碍，即脂毒性，这可以解释PCOS女性的高雄激素血症和胰岛素抵抗。文献表明，雄激素分泌组织过度暴露于NEFA和/或NEFA代谢缺陷可能诱导雄激素生物合成，导致脂毒性作用。事实上，脂毒性可引发雄激素对胰岛素、促黄体生成素（LH）和促肾上腺皮质激素（ACTH）的高反应性。在大多数PCOS女性中，脂毒性还会导致胰岛素抵抗，诱发代偿性高胰岛素血症，进而可能进一步加重高雄激素血症。许多旨在提高胰岛素敏感性的方法也能降低脂毒性，并已被证明可治疗PCOS高雄激素血症。此外，我们团队及其他研究发现，2型血管紧张素II受体（AT2R）激活能够改善脂毒性。我们使用C21/M24提供了证据，表明在胰岛素抵抗大鼠模型中，AT2R激活可改善脂肪细胞大小和胰岛素敏感性，在PCOS肥胖大鼠模型中可改善雄激素水平。综上所述，这些发现表明脂毒性在PCOS发生中起重要作用，且肾素-血管紧张素系统（RAS）作为PCOS治疗的新靶点。
