SUN-015 Developmental Programming: Depot-Specific Inflammatory State and Distribution of Thermogenic Adipocytes Programmed by Gestational Testosterone Excess

Prenatal testosterone excess induces insulin resistance, dyslipidemia and cardiovascular defects in ewes. Considering adipose depots influence systemic metabolic status, disruptions in visceral (VAT), subcutaneous (SAT), pericardiac (PCAT) and perirenal (PRAT) adipose depots may contribute to these metabolic defects. While the changes in PCAT and PRAT in the prenatal T-treated sheep are unknown, we found an increase in the oxidative stress and inflammatory state in the VAT but not SAT, while insulin sensitivity is maintained in both depots (Biol Reprod 2016;94:113). Although all four depots are rich in white adipocytes that specialize in lipid storage, it is not clear what underlies the depot-specific differences. A potential contributor may relate to depot-specific differences in presence of brown/beige adipocytes. Brown/beige unlike white adipocytes are thermogenically active due to their expression of uncoupled protein 1 (UCP1), which uncouples mitochondrial oxidative phosphorylation to release stored energy as heat. Because they favor lipid utilization rather than storage they promote a metabolically healthy phenotype. We hypothesized that the relative distribution of brown/beige adipocytes may contribute to the depot-specific changes in inflammatory state. To test this, adipose depots from control (n=6) and prenatal T- (100mg T propionate twice a week from days 30-90 of gestation)-treated (n=5) female sheep were studied at 21 months of age. The changes in expression of inflammatory and thermogenic adipocyte markers were assessed by real time RT-PCR and data analyzed by Student’s t-test and Cohen’s effect size analysis. Prenatal T-treatment induced 1) significant increase in inflammatory cytokine interleukin 6 in VAT and PRAT while decreasing it in PCAT 2) significant increase in tumor necrosis factor in the VAT and a trend (evident by effect size analysis only) for an increase in SAT and PCAT and 3) significant increase in PRAT and a trend toward increase in the macrophage marker CD68 expression in VAT. Among the thermogenic gene markers, the expression of UCP1 was significantly increased in VAT and PCAT with a trend for an increase in PRAT. The expression of UCP2 and PPAR gamma co-activator 1 beta (PPARGC1B) were also significantly elevated in VAT with a trend for an increase in SAT. These findings are indicative of depot-specific differences in prenatal T-induced inflammatory status with effects being pronounced in VAT compared to other depots. The increases in thermogenic markers in adipose depots do not support our hypothesis but rather are reflective of a compensatory response to promote adipose depot insulin sensitivity and may have a bearing on function of organs in the proximity of respective depots. These findings are likely of translational significance in metabolic disorders associated with hyperandrogenic state.