Developmental Programming of Metabolic Dysfunctionsby Tes tos terone Excess

Developmental programming is a primitive mechanism that isevident during sex determination. Its role is becoming apparentin the developmental origin of diseases. Because s teroids orchestratethe communication between the intrauterine environmentand the developing fetus, inappropriate exposure to sex s teroidsor environmental s teroid mimics during critical windows of differentiationcould disrupt the developmental trajectory of organsys tems leading to adult dysfunctions. Experimental manipulationof the prenatal s teroid environment provides a powerfultool for unders tanding mechanisms that underlie developmentalmalprogramming of metabolic sys tems. This presentation willaddress how prenatal exposure to excess tes tos terone perturbsthe metabolic homeos tasis in female sheep, a precocial model oftranslational importance to Polycys tic Ovary Syndrome (PCOS),a major infertility disorder affecting reproductive aged women.Our s tudies provided causal evidence that in utero exposure toexcess tes tos terone leads to peripheral insulin resis tance and tissue-specific changes in insulin sensitivity with liver and musclebut not adipose tissue being insulin resis tant. In addition, prenataltes tos terone excess also programs defects at the adipocytelevel manifes ted as reduced adipocyte size reflective of defects inadipogenesis, ectopic lipid accumulation that includes a Non-alcoholicfatty liver disease (NAFLD) liver phenotype, and hyper hypertension.Prenatal and pos tnatal intervention with either antiandrogen(flutamide) or insulin sensitizer (Rosiglitazone) partiallyprevented or ameliorated the prenatal tes tos terone-programmedchanges in mediators of insulin sensitivity and adipocyte defectssugges ting that both pathways are critical for the programmingand maintenance of the prenatal tes tos terone-induced changes ininsulin sensitivity and adipose defects. Because prenatal tes tosterone-treated sheep completely recapitulates the reproductiveand metabolic characteris tics of women with PCOS, these findingsfrom the sheep model of PCOS phenotype are of translationalrelevance.