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Women with polycystic ovary syndrome (PCOS) often manifest insulin resistance. Using a sheep model of PCOS-like phenotype, we explored the contribution of androgen and insulin in programming and maintaining disruptions in insulin signaling in metabolic tissues. Phosphorylation of AKT, ERK, GSK3β, mTOR, and p70S6K was examined in liver, muscle and adipose tissue of control, prenatal testosterone (T)-, prenatal T+ androgen antagonist (flutamide), and prenatal T+ insulin sensitizer (rosiglitazone)-treated fetuses and two-year-old females. Insulin-stimulated phospho (p)-AKT was evaluated in control, prenatal T-, prenatal T+ postnatal flutamide-, and prenatal T+ postnatal rosiglitazone-treated females at 3 years of age. GLUT4 expression was evaluated in the muscle at all time points. Prenatal T-treatment increased mTOR, p-p70S6K, and p-GSK3β levels in the fetal liver with androgen antagonist and insulin sensitizer preventing the mTOR increase. Both interventions had partial effect in preventing the increase in p-GSK3β. In the fetal muscle, prenatal T excess decreased p-GSK3β and GLUT4. The decrease in muscle p-GSK3β was partially prevented by insulin sensitizer co-treatment. Both interventions partially prevented the decrease in GLUT4. Prenatal T-treatment had no effect on basal expression of any of the markers in two-year-old females. At year 3, prenatal T-treatment prevented the insulin-stimulated increase in p-AKT in liver and muscle, but not in adipose tissue, and neither postnatal intervention restored p-AKT response to insulin stimulation. Our findings provide evidence that prenatal T excess changes insulin sensitivity in a tissue- and development-specific manner and that both androgens and insulin may be involved in the programming of these metabolic disruptions.

Developmental Programming: Prenatal Testosterone Excess and Insulin Signaling Disruptions in Female Sheep1