Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
Section of Molecular Medicine, Department of Internal Medicine, Center for Precision Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
Am J Physiol Endocrinol Metab. 2022 Oct 1;323(4):E336-E353. doi: 10.1152/ajpendo.00263.2021. Epub 2022 Jul 20.
Infants born to obese mothers are more likely to develop metabolic disease, including glucose intolerance and hepatic steatosis, in adult life. We examined the effects of maternal obesity on the transcriptome of skeletal muscle and liver tissues of the near-term fetus and 3-mo-old offspring in mice born to dams fed a high-fat and -sugar diet. Previously, we have shown that male, but not female, offspring develop glucose intolerance, insulin resistance, and liver steatosis at 3 mo old. Female C57BL6/J mice were fed normal chow or an obesogenic high-calorie diet before mating and throughout pregnancy. RNAseq was performed on the liver and gastrocnemius muscle following collection from fetuses on () as well as from 3-mo-old offspring from obese dams and control dams. Significant genes were generated for each sex, queried for enrichment, and modeled to canonical pathways. RNAseq was corroborated by protein quantification in offspring. The transcriptomic response to maternal obesity in the liver was more marked in males than females. However, in both male and female offspring of obese dams, we found significant enrichment for fatty acid metabolism, mitochondrial transport, and oxidative stress in the liver transcriptomes as well as decreased protein concentrations of electron transport chain members. In skeletal muscle, pathway analysis of gene expression revealed sexual dimorphic patterns, including metabolic processes of fatty acids and glucose, as well as PPAR, AMPK, and PI3K-Akt signaling pathways. Transcriptomic responses to maternal obesity in skeletal muscle were more marked in female offspring than males. Female offspring had greater expression of genes associated with glucose uptake, and protein abundance reflected greater activation of mTOR signaling. Skeletal muscle and livers in mice born to obese dams had sexually dimorphic transcriptomic responses that changed from the fetus to the adult offspring. These data provide insights into mechanisms underpinning metabolic programming in maternal obesity. Transcriptomic data support that fetuses of obese mothers modulate metabolism in both muscle and liver. These changes were strikingly sexually dimorphic in agreement with published findings that male offspring of obese dams exhibit pronounced metabolic disease earlier. In both males and females, the transcriptomic responses in the fetus were different than those at 3 mo, implicating adaptive mechanisms throughout adulthood.
肥胖母亲所生的婴儿在成年后更有可能患上代谢疾病，包括葡萄糖不耐受和肝脂肪变性。我们研究了肥胖母亲对高脂肪高糖饮食喂养的母鼠所生的近足月胎儿和 3 月龄幼鼠骨骼肌和肝脏组织转录组的影响。此前，我们已经表明，雄性而非雌性后代在 3 月龄时会出现葡萄糖不耐受、胰岛素抵抗和肝脂肪变性。雌性 C57BL6/J 小鼠在交配前和整个孕期都被喂食正常饲料或致肥胖的高热量饮食。在收集肥胖母鼠和对照母鼠所生的胎儿（）以及 3 月龄幼鼠的肝脏和比目鱼肌后，进行了 RNAseq。为每个性别生成了显著基因，对其进行了富集分析，并构建了经典途径模型。RNAseq 结果通过后代的蛋白质定量进行了验证。与肥胖母鼠相关的肝转录组对母体肥胖的反应在雄性中比雌性更明显。然而，在肥胖母鼠所生的雄性和雌性后代中，我们发现肝转录组中脂肪酸代谢、线粒体转运和氧化应激显著富集，电子传递链成员的蛋白质浓度降低。在骨骼肌中，基因表达的途径分析揭示了性别二态模式，包括脂肪酸和葡萄糖的代谢过程，以及 PPAR、AMPK 和 PI3K-Akt 信号通路。母体肥胖对骨骼肌的转录组反应在雌性后代中比雄性更明显。雌性后代与葡萄糖摄取相关的基因表达增加，并且 mTOR 信号的激活反映了蛋白质丰度的增加。肥胖母鼠所生的小鼠的骨骼肌和肝脏具有性别二态性的转录组反应，从胎儿到成年后代发生了变化。这些数据为母体肥胖引起的代谢编程的机制提供了见解。转录组数据表明肥胖母亲的胎儿在肌肉和肝脏中都调节代谢。这些变化在雄性后代中表现出明显的性别二态性，这与肥胖母鼠的雄性后代更早出现明显代谢疾病的发表研究结果一致。在雄性和雌性中，胎儿的转录组反应与 3 月龄时的反应不同，这表明整个成年期都存在适应性机制。
