Role of Lipotoxicity and Contribution of the Renin-Angiotensin System in the Development of Polycystic Ovary Syndrome

Figure 1

Proposed cellular mechanisms involved in insulin-stimulated androgen biosynthesis, PCOS-associated defects, and free fatty acid-induced insulin resistance and androgen production, together with AT2R and PPARγ actions. Serine phosphorylation of IRS-1 prevents its binding with PI3K and inhibits insulin signaling. Moreover, serine phosphorylation of P450c17 increases its 17,20-lyase activity and thus androgen biosynthesis. Interestingly, serine phosphorylation of IRS-1 is constitutively increased in PCOS women and increased by nonesterified fatty acid (NEFA) overload. Insulin-stimulated androgen production has been shown to be reduced by specific inhibition of PI3K and increased by specific inhibition of MEK. MEK/ERK activity was found to be constitutively reduced in PCOS women and inhibited by NEFAs. It was also suggested that P450c17 activity may be stimulated by other players of the MAPK pathway, such as MKK3/6-p38 and MKK4/7-JNK, whose activities are not reduced, and may be even increased, in women with PCOS. Adapted from [10].