Developmental programming: differential effects of prenatal testosterone excess on insulin target tissues

Area of Science:

• Endocrinology
• Reproductive Biology
• Metabolic Syndrome

Background:

• Polycystic ovarian syndrome (PCOS) is a leading cause of infertility and is strongly associated with insulin resistance in women of reproductive age.
• Understanding the molecular mechanisms underlying insulin resistance in PCOS is crucial for developing effective therapeutic strategies.

Purpose of the Study:

• To investigate the impact of prenatal exposure to excess testosterone on insulin receptor (IR) signaling pathways.
• To determine tissue-specific alterations in gene expression related to insulin action in a sheep model mimicking PCOS.

Main Methods:

• Adult sheep exposed to testosterone in utero were compared to control sheep.
• Quantitative analysis of mRNA expression for insulin receptor isoforms and key signaling pathway components was performed in liver, muscle, and adipose tissue.

Main Results:

• Prenatal testosterone excess altered gene expression in a tissue-specific manner.
• In the liver, reduced expression of IR-B, IRS-2, Akt, and PPARγ was observed, alongside increased rictor and eIF4E.
• Muscle tissue showed an increased IR-A to IR-B ratio and elevated IRS-1 and rictor, with decreased ERK1, while adipose tissue exhibited increased IRS-2, PI3K, PPARγ, and mTOR.

Conclusions:

• Prenatal testosterone excess induces significant, tissue-specific changes in insulin signaling pathways.
• These molecular alterations support the hypothesis that prenatal androgen excess contributes to insulin resistance in PCOS by disrupting peripheral tissue insulin sensitivity, particularly in the liver and muscle.