Evidence of increased hypoxia signaling in fetal liver from maternal nutrient restriction in mice

Pediatr Res. 2020 Feb;87(3):450-455. doi: 10.1038/s41390-019-0447-z. Epub 2019 Jun 11.


Background: 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.

Methods: 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.

Results: 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.

Conclusion: Although a moderate impact, these data support evidence of fetal adaptation to reduced nutrients by increased hypoxia signaling in the liver.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptation, Physiological
  • Animal Nutritional Physiological Phenomena*
  • Animals
  • Animals, Newborn
  • Disease Models, Animal
  • Female
  • Fetal Growth Retardation / genetics
  • Fetal Growth Retardation / metabolism*
  • Fetal Growth Retardation / physiopathology
  • Fetal Hypoxia / genetics
  • Fetal Hypoxia / metabolism*
  • Fetal Hypoxia / physiopathology
  • Gene Expression Regulation, Developmental
  • Gestational Age
  • Liver / growth & development
  • Liver / metabolism*
  • Male
  • Maternal Nutritional Physiological Phenomena*
  • Mice
  • Nutritional Status*
  • Pregnancy
  • Prenatal Exposure Delayed Effects
  • Signal Transduction* / genetics

Grant support