Electronic Thesis and Dissertation Repository


Doctor of Philosophy



Collaborative Specialization

Developmental Biology


Han, Victor VKM.


Intrauterine growth restriction (IUGR) is a pregnancy condition where fetal growth is suboptimal, resulting in an infant born small for gestational age (<10th percentile) and is associated with metabolic disorders such as type 2 diabetes in adulthood. This study aims to understand tissue-specific adaptations to fetal undernutrition which predispose the individual to metabolic disorders in adulthood. A model of growth restriction in mice was established using 70% of maternal ad libitum total food (g) (E6.5-birth). At weaning, male offspring received standard chow or a HFHS diet. Body weight and random blood glucose levels were measured at 6 months. To assess metabolism at 6 or 7 months, glucose tolerance, pyruvate challenge and hepatic portal vein insulin challenge tests were administered and serum peptide markers for obesity and diabetes were measured. Metabolic cages were also used at 2 and 7 months to measure activity, food intake and respiratory exchange ratios (RERs). Adult liver, adipose and skeletal muscle and fetal liver was collected for RNA sequencing. Maternal nutrient restricted (MNR) offspring were growth restricted with disproportionately smaller fetal livers. 19% of standard chow-fed MNR offspring became glucose intolerant. On an isocaloric high-fat high-sugar diet no differences in MNR growth or glucose metabolism were detected. However, RERs were reduced at all timepoints in MNR on a HFHS relative to MNR on standard chow. Differences in transcription of genes involved in hypoxia signalling were detected and HIF-2a and HIF-3a proteins were increased in fetal liver of MNR offspring. Genes differentially expressed in the fetus were not differentially expressed at 6 months. Gene expression of metabolically regulatory transcripts in liver, adipose and skeletal muscle did not differ in all MNR and glucose intolerant MNR relative to controls. This model results in a susceptible and non-susceptible population of maternal nutrient restricted offspring and supports the concept of hypoxia signalling contributing to fetal adaptations. Understanding adaptations in hepatic hypoxia signalling in response to fetal undernutrition and how they vary in susceptible and unsusceptible populations will provide insight into how fetal nutrition can influence adult metabolism.