Prenatal Metformin Exposure in a Maternal High Fat Diet Mouse Model Alters the Transcriptome and Modifies the Metabolic Responses of the Offspring
Prenatal Metformin Exposure in a Maternal High Fat Diet Mouse Model Alters the Transcriptome and Modifies the Metabolic Responses of the Offspring
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DOI：
10.1371/journal.pone.0115778
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发表时间：
2014-12-26
期刊：
影响因子：
3.7
通讯作者：
Koulu, Markku
中科院分区：
文献类型：
--
作者：
Salomaki, Henriikka;Heinaniemi, Merja;Koulu, Markku
目的：尽管二甲双胍在代谢困难的妊娠中广泛使用，但对后代代谢的长期影响尚不清楚。我们研究了小鼠代谢障碍妊娠期间产前二甲双胍暴露的长期影响。材料和方法：雌性小鼠在妊娠前和妊娠期间接受高脂肪饮食（HFD）。在妊娠期 E0.5 至 E17.5 期间服用二甲双胍。雄性和雌性后代断奶后采用常规饮食 (RD)，并在成年期（10-11 周）接受 HFD。研究期间测量了体重和一些代谢参数（例如身体成分和葡萄糖耐量）。在出生后第 4 天的单独实验中，对雄性后代的肝脏和皮下脂肪组织进行了微阵列和随后的通路分析。结果：产前二甲双胍暴露改变了后代对 HFD 的反应。在 HFD 阶段，暴露于二甲双胍的后代体重和脂肪组织增加较少。此外，产前接触二甲双胍可以预防 HFD 引起的糖耐量损害。微阵列和注释分析揭示了二甲双胍引起的几种代谢途径的变化，其中电子传递链（ETC）在新生儿肝脏和脂肪组织中均受到显着影响。结论：本研究表明，产前二甲双胍暴露对后代的葡萄糖耐量和 HFD 期间的脂肪量积累具有有益影响。新生儿时期获得的转录组数据表明，线粒体 ATP 产生和脂肪细胞分化所涉及的基因受到重大影响，提示了成年期代谢表型改善的机制途径。
Aims: Despite the wide use of metformin in metabolically challenged pregnancies, the long-term effects on the metabolism of the offspring are not known. We studied the long-term effects of prenatal metformin exposure during metabolically challenged pregnancy in mice.Materials and Methods: Female mice were on a high fat diet (HFD) prior to and during the gestation. Metformin was administered during gestation from E0.5 to E17.5. Male and female offspring were weaned to a regular diet (RD) and subjected to HFD at adulthood (10-11 weeks). Body weight and several metabolic parameters (e.g. body composition and glucose tolerance) were measured during the study. Microarray and subsequent pathway analyses on the liver and subcutaneous adipose tissue of the male offspring were performed at postnatal day 4 in a separate experiment.Results: Prenatal metformin exposure changed the offspring's response to HFD. Metformin exposed offspring gained less body weight and adipose tissue during the HFD phase. Additionally, prenatal metformin exposure prevented HFD-induced impairment in glucose tolerance. Microarray and annotation analyses revealed metformin-induced changes in several metabolic pathways from which electron transport chain (ETC) was prominently affected both in the neonatal liver and adipose tissue.Conclusion: This study shows the beneficial effects of prenatal metformin exposure on the offspring's glucose tolerance and fat mass accumulation during HFD. The transcriptome data obtained at neonatal age indicates major effects on the genes involved in mitochondrial ATP production and adipocyte differentiation suggesting the mechanistic routes to improved metabolic phenotype at adulthood.