Lack of metformin effect on mouse embryo AMPK activity: implications for metformin treatment during pregnancy
Lack of metformin effect on mouse embryo AMPK activity: implications for metformin treatment during pregnancy
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DOI：
10.1002/dmrr.2451
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发表时间：
2014-01-01
影响因子：
8
通讯作者：
Loeken, Mary R.
中科院分区：
文献类型：
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作者：
Lee, Hyung-yul;Wei, Dan;Loeken, Mary R.
研究背景妊娠糖尿病时，母体高血糖诱导的胚胎氧化应激可刺激胚胎中腺苷一磷酸活化蛋白激酶（AMPK）的表达。AMPK的刺激破坏胚胎基因表达并导致神经管缺陷。据报道，妊娠早期服用的二甲双胍可刺激AMPK活性。因此，改善的贫血控制的益处可以通过刺激胚胎AMPK活性来抵消。在这里，我们调查了二甲双胍是否可以刺激AMPK活性在小鼠胚胎中，并可能对胚胎基因表达和神经管defects.MethodsPregnant diabetes mice给药二甲双胍开始在怀孕的第一天。研究母体和胚胎AMPK [磷酸化AMPK（Thr 172）相对于总AMPK]的激活、Pax 3（神经管闭合所需的基因）的表达和神经管缺陷。小鼠胚胎干细胞作为胚胎神经上皮细胞培养模型，研究二甲双胍对AMPK和Pax 3表达的影响。结果二甲双胍对胚胎或母体骨骼肌中AMPK没有影响，但增加了母体肝脏中活化的AMPK。二甲双胍不抑制Pax 3表达或增加神经管缺陷。然而，二甲双胍增加了小鼠胚胎干细胞活化的AMPK并抑制了Pax 3的表达。编码二甲双胍转运蛋白的Mate 1/Slc 47 a1和Oct 3/Slc 22 a在胚胎中的表达水平几乎检测不到。体内对小鼠胚胎缺乏影响可能是由于缺乏二甲双胍转运蛋白，表明二甲双胍对血糖控制的益处不会被刺激胚胎AMPK活性和随后的胚胎病版权所有（c）2013约翰威利父子有限公司
BackgroundAdenosine monophosphate-activated protein kinase (AMPK) is stimulated in embryos during diabetic pregnancy by maternal hyperglycaemia-induced embryo oxidative stress. Stimulation of AMPK disrupts embryo gene expression and causes neural tube defects. Metformin, which may be taken during early pregnancy, has been reported to stimulate AMPK activity. Thus, the benefits of improved glycaemic control could be offset by stimulated embryo AMPK activity. Here, we investigated whether metformin can stimulate AMPK activity in mouse embryos and can adversely affect embryo gene expression and neural tube defects.MethodsPregnant nondiabetic mice were administered metformin beginning on the first day of pregnancy. Activation of maternal and embryo AMPK [phospho-AMPK (Thr172) relative to total AMPK], expression of Pax3, a gene required for neural tube closure, and neural tube defects were studied. Mouse embryonic stem cells were used as a cell culture model of embryonic neuroepithelium to study metformin effects on AMPK and Pax3 expression.ResultsMetformin had no effect on AMPK in embryos or maternal skeletal muscle but increased activated AMPK in maternal liver. Metformin did not inhibit Pax3 expression or increase neural tube defects. However, metformin increased activated AMPK and inhibited Pax3 expression by mouse embryonic stem cells. Mate1/Slc47a1 and Oct3/Slc22a, which encode metformin transporters, were expressed at barely detectable levels by embryos.ConclusionsAlthough metformin can have effects associated with diabetic embryopathy in vitro, the lack of effects on mouse embryos in vivo may be due to lack of metformin transporters and indicates that the benefits of metformin on glycaemic control are not counteracted by stimulation of embryo AMPK activity and consequent embryopathy. Copyright (c) 2013 John Wiley & Sons, Ltd.