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 (n = 7) and prenatal T-treated (n = 6) female sheep. Prenatal T-treatment increased lipid droplet and metabolism genes PPARA and PLIN1 in liver, SREBF and PLIN1 in muscle and 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.

产前睾酮（T）治疗的雌性绵羊表现出外周胰岛素抵抗和胰岛素敏感性的组织特异性变化，肝脏和肌肉表现出胰岛素抵抗并伴有炎症、氧化和脂毒性状态。相比之下，内脏（VAT）和皮下（SAT）脂肪组织对胰岛素敏感，尽管VAT表现出炎症和氧化状态的变化。我们假设，产前 T 诱导的组织特异性胰岛素抵抗变化是由 DNA 和组蛋白修饰酶变化驱动的脂质储存和代谢基因表达破坏引起的。对从对照 (n = 7) 和产前 T 处理 (n = 6) 雌性绵羊收集的肝脏、肌肉和 4 种脂肪（VAT、SAT、心外膜 [ECAT] 和肾周 [PRAT]）库中的基因表达变化进行了评估。产前 T 治疗增加了肝脏中的脂滴和代谢基因PPARA和PLIN1 ，肌肉中的SREBF和PLIN1 ，以及 PRAT 中PLIN2的减少趋势。在表观遗传修饰酶中，产前 T 治疗增加了 1) 肝脏中DNMT1和 VAT、PRAT、肌肉和肝脏中DNMT3A的表达； 2) ECAT中的HDAC1 、肌肉中的HDAC2以及VAT中的HDAC3减少； 3）VAT和ECAT中的EP300 ； 4) VAT 中的KDM1A伴随肝脏组蛋白乙酰化的增加。肝脏和肌肉中脂质储存和代谢基因的增加与这些组织中的脂毒性一致，组蛋白乙酰化增加可能导致肝脏PPARA增加。 这些发现表明，产前接受 T 治疗的绵羊的代谢缺陷可能是由关键基因的变化引起的，部分是由表观遗传修饰酶的组织特异性变化介导的。