Transcriptomic responses are sex-dependent in the skeletal muscle and liver in offspring of obese mice.
Transcriptomic responses are sex-dependent in the skeletal muscle and liver in offspring of obese mice.
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肥胖小鼠后代骨骼肌和肝脏的转录组反应具有性别依赖性。
DOI：
10.1152/ajpendo.00263.2021
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Jansson,Thomas
中科院分区：
文献类型：
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作者：
Kelly,AmyC;JRosario,Fredrick;Chan,Jeannie;Cox,LauraA;Powell,TheresaL;Jansson,Thomas
肥胖母亲所生的婴儿在成年后更有可能患上代谢性疾病，包括葡萄糖耐受不良和肝脏脂肪变性。我们研究了母体肥胖对高脂高糖饮食母鼠所生的近足月胎儿和3个月大后代骨骼肌和肝脏组织转录组的影响。以前，我们已经表明，男性，而不是女性，后代发展葡萄糖耐受不良，胰岛素抵抗，和肝脏脂肪变性在3个月大。雌性C57BL6/J小鼠在交配前和整个妊娠期间喂食正常食物或致肥胖高热量饮食。在从胚胎第18.5天（E18.5）的胎儿以及从肥胖母鼠和对照母鼠的3月龄后代收集后，对肝脏和腓肠肌进行RNAseq。为每种性别生成显著基因，查询富集，并建模为典型途径。通过后代中的蛋白质定量证实了RNAseq。在肝脏中对母体肥胖的转录组反应在男性中比女性更显著。然而，在肥胖母鼠的雄性和雌性后代中，我们发现肝脏转录组中脂肪酸代谢、线粒体转运和氧化应激显著富集，以及电子传递链成员的蛋白质浓度降低。在骨骼肌中，基因表达的通路分析揭示了性二态模式，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。骨骼肌中对母体肥胖的转录组反应在雌性后代中比雄性后代更显著。雌性后代具有更高的与葡萄糖摄取相关的基因表达，蛋白质丰度反映了mTOR信号传导的更大激活。肥胖母鼠所生小鼠的骨骼肌和肝脏具有从胎儿到成年后代的性二态转录组反应。这些数据提供了对支持母体肥胖代谢程序的机制的深入了解。新&值得注意的转录组学数据支持肥胖母亲的胎儿调节肌肉和肝脏的代谢。这些变化是惊人的性二态性与发表的研究结果，即肥胖的母鼠的雄性后代表现出明显的代谢疾病的早期协议。在男性和女性中，胎儿的转录组反应与3个月时不同，这意味着整个成年期的适应机制。
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 onembryonic day 18.5(E18.5) 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.NEW & NOTEWORTHYTranscriptomic 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.