Abstract
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.
Highlights
Polycystic ovary syndrome (PCOS) is a common condition affecting 6–8% of women of childbearing age [1]
We showed in lean normoinsulinemic PCOS women who were not insulin resistant based on a glucoseinsulin clamp that lowering their insulin secretion with diazoxide for 8 days was associated with a significant drop in their free testosterone and androstenedione levels [36]. Since their insulin levels were normal at the baseline, this study suggests that lean, insulin-sensitive women with PCOS display hyperresponsiveness to insulin, which could be the case for all women with PCOS
In fibroblast [42] and muscle cells [43], it was found that serine phosphorylation of the insulin receptor or insulin receptor substrate- (IRS-) 1 is constitutively increased in PCOS women, which was associated with a reduction in tyrosine phosphorylation of the insulin receptor and IRS [42] and reduced PI3K activity
Summary
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. In most PCOS women, lipotoxicity causes insulin resistance, inducing compensatory hyperinsulinemia, and may further increase hyperandrogenemia. 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
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