Developmental programming: Prenatal testosterone-induced changes in epigenetic modulators and gene expression in metabolic tissues of female sheep.

Prenatal testosterone (T)-treated female sheep manifest peripheral insulin resistance and tissue-specific changes in insulin sensitivity with liver and muscle manifesting insulin resistance accompanied by inflammatory, oxidative and lipotoxic state. In contrast, visceral (VAT) and subcutaneous (SAT) adipose tissues are insulin sensitive in spite of VAT manifesting changes in inflammatory and oxidative state. We hypothesized that prenatal T-induced changes in tissue-specific insulin resistance arise from disrupted lipid storage and metabolism gene expression driven by changes in DNA and histone modifying enzymes. Changes in gene expression were assessed in liver, muscle and 4 adipose (VAT, SAT, epicardiac [ECAT] and perirenal [PRAT]) depots collected from control and prenatal T-treated female sheep. Prenatal T-treatment increased lipid droplet and metabolism genes PPARA and PLIN1 in liver, SREBF and PLIN1 in muscle and showed a trend for decrease in PLIN2 in PRAT. Among epigenetic modifying enzymes, prenatal T-treatment increased expression of 1) DNMT1 in liver and DNMT3A in VAT, PRAT, muscle and liver; 2) HDAC1 in ECAT, HDAC2 in muscle with decrease in HDAC3 in VAT; 3) EP300 in VAT and ECAT; and 4) KDM1A in VAT with increases in liver histone acetylation. Increased lipid storage and metabolism genes in liver and muscle are consistent with lipotoxicity in these tissues with increased histone acetylation likely contributing to increased liver PPARA. These findings are suggestive that metabolic defects in prenatal T-treated sheep may arise from changes in key genes mediated, in part, by tissue-specific changes in epigenetic-modifying enzymes.