Department of Biochemistry, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada.
Children's Health Research Institute, London, ON, Canada.
Pediatr Res. 2020 Feb;87(3):450-455. doi: 10.1038/s41390-019-0447-z. Epub 2019 Jun 11.
Intrauterine growth restriction (IUGR) is a pregnancy condition where fetal growth is reduced, and offspring from IUGR pregnancies are at increased risk for type II diabetes as adults. The liver is susceptible to fetal undernutrition experienced by IUGR infants and animal models of growth restriction. This study aimed to examine hepatic expression changes in a maternal nutrient restriction (MNR) mouse model of IUGR to understand fetal adaptations that influence adult metabolism.
Liver samples of male offspring from MNR (70% of ad libitum starting at E6.5) or control pregnancies were obtained at E18.5 and differential expression was assessed by RNAseq and western blots.
Forty-nine differentially expressed (FDR < 0.1) transcripts were enriched in hypoxia-inducible pathways including Fkbp5 (1.6-fold change), Ccng2 (1.5-fold change), Pfkfb3 (1.5-fold change), Kdm3a (1.2-fold change), Btg2 (1.6-fold change), Vhl (1.3-fold change), and Hif-3a (1.3-fold change) (FDR < 0.1). Fkbp5, Pfkfb3, Kdm3a, and Hif-3a were confirmed by qPCR, but only HIF-2a (2.2-fold change, p = 0.002) and HIF-3a (1.3 p = 0.03) protein were significantly increased.
Although a moderate impact, these data support evidence of fetal adaptation to reduced nutrients by increased hypoxia signaling in the liver.
宫内生长受限（IUGR）是一种胎儿生长受限的妊娠情况，IUGR 妊娠的后代成年后患 II 型糖尿病的风险增加。肝脏容易受到 IUGR 婴儿和生长受限动物模型中胎儿营养不良的影响。本研究旨在检查母体营养限制（MNR）IUGR 小鼠模型中的肝表达变化，以了解影响成人代谢的胎儿适应。
从 MNR（从 E6.5 开始的 70%自由进食）或对照妊娠的雄性后代的肝组织样本在 E18.5 时获得，并通过 RNAseq 和 Western blot 评估差异表达。
49 个差异表达（FDR<0.1）的转录本在缺氧诱导途径中富集，包括 Fkbp5（1.6 倍变化）、Ccng2（1.5 倍变化）、Pfkfb3（1.5 倍变化）、Kdm3a（1.2 倍变化）、Btg2（1.6 倍变化）、Vhl（1.3 倍变化）和 Hif-3a（1.3 倍变化）（FDR<0.1）。通过 qPCR 确认了 Fkbp5、Pfkfb3、Kdm3a 和 Hif-3a，但只有 HIF-2a（2.2 倍变化，p=0.002）和 HIF-3a（1.3 p=0.03）蛋白显著增加。
尽管影响较小，但这些数据支持了肝脏中缺氧信号增加表明胎儿适应减少营养的证据。
