Reconciling the nutritional and glucocorticoid hypotheses of fetal programming
Reconciling the nutritional and glucocorticoid hypotheses of fetal programming
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DOI：
10.1096/fj.12-203489
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发表时间：
2012-05-01
期刊：
影响因子：
4.8
通讯作者：
Seckl, Jonathan R.
中科院分区：
文献类型：
--
作者：
Cottrell, Elizabeth C.;Holmes, Megan C.;Seckl, Jonathan R.
胎儿生长受限与成人心脏代谢和神经精神疾病风险增加相关。母体营养不良[特别是低蛋白（LP）饮食]和应激/糖皮质激素暴露都会降低胎儿生长，并导致成年后代持续异常（编程）。使糖皮质激素失活的胎盘11 β-羟基类固醇脱氢酶-2（11 β-HSD 2）的缺乏可通过LP饮食减少，并已被认为是一种统一的机制。在这里，我们探讨了糖皮质激素和胎盘11 β-HSD 2在饮食规划中的重要性。妊娠小鼠在整个妊娠期间喂食对照或等热量LP饮食。LP饮食首先升高胎儿糖皮质激素水平，然后降低胎盘生长，最后使近足月胎儿体重下降17%。而LP饮食降低胎盘11 β-HSD 2活性近25%，与以前的报告一致，活性增加20和40%之间的早期年龄，这意味着糖皮质激素过度在LP胎儿发生通过11 β-HSD 2非依赖性机制。与此相一致，杂合11 β-HSD 2（+/-）杂交显示，尽管LP和11 β-HSD 2缺陷都会降低胎儿生长，但LP确实独立于11 β-HSD 2发挥作用。相反，LP饮食诱导胎儿下丘脑-垂体-肾上腺轴本身。因此，母体营养不良和胎盘11 β-HSD 2缺乏症通过不同的过程来延缓胎儿生长，两者都涉及胎儿胎盘过度分泌糖皮质激素，但来源不同。Cottrell，E. C.的方法，霍姆斯，M。C.的方法，利文斯通，D。E、凯农角J.，Seckl，J. R.证实胎儿编程的营养和糖皮质激素假设。FASEB J.26，1866-1874（2012）。www.fasebj.org
Fetal growth restriction associates with increased risk of adult cardiometabolic and neuropsychiatric disorders. Both maternal malnutrition [notably a low-protein (LP) diet] and stress/glucocorticoid exposure reduce fetal growth and cause persisting abnormalities (programming) in adult offspring. Deficiency of placental 11 beta-hydroxysteroid dehydrogenase-2 (11 beta-HSD2), which inactivates glucocorticoids, is reduced by an LP diet and has been proposed as a unifying mechanism. Here, we explored the importance of glucocorticoids and placental 11 beta-HSD2 in dietary programming. Pregnant mice were fed a control or isocaloric LP diet throughout gestation. The LP diet first elevated fetal glucocorticoid levels, then reduced placental growth, and finally decreased fetal weight near term by 17%. Whereas the LP diet reduced placental 11 beta-HSD2 activity near term by similar to 25%, consistent with previous reports, activity was increased between 20 and 40% at earlier ages, implying that glucocorticoid overexposure in LP fetuses occurs via 11 beta-HSD2-independent mechanisms. Consistent with this, heterozygous 11 beta-HSD2(+/-) crosses showed that although both LP and 11 beta-HSD2 deficiency reduced fetal growth, LP indeed acted independently of 11 beta-HSD2. Instead, the LP diet induced the fetal hypothalamic-pituitary-adrenal axis per se. Thus, maternal malnutrition and placental 11 beta-HSD2 deficiency act via distinct processes to retard fetal growth, both involving fetoplacental overexposure to glucocorticoids but from distinct sources.-Cottrell, E. C., Holmes, M. C., Livingstone, D. E., Keynon, C. J., Seckl, J. R. Reconciling the nutritional and glucocorticoid hypotheses of fetal programming. FASEB J. 26, 1866-1874 (2012). www.fasebj.org