The fetal liver in intrauterine growth restricted pregnancies caused by placental insufficiency (PI-IUGR) develops metabolic adaptations to hypoxia and decreased placenta-to-fetus nutrient transfer. These adaptations include an early activation of gluconeogenesis and resistance to insulin's suppression of hepatic glucose production. This is important because while these metabolic adaptations may be necessary to ensure fetal survival, they also can lead to pathological conditions later in life, including type diabetes (T2DM). Importantly, the early mechanisms responsible for these metabolic reprogramming adaptations in the PI-IUGR fetal liver are largely unknown. Our working hypothesis is that hypoxia from placental insufficiency induces metabolic reprogramming, defined by increased glycolysis and decreased glucose oxidation, via a HIF and FOXO1 mechanism that also results in impaired insulin suppression of glucose production in the PI-IUGR fetal liver. The goal of this proposal is to determine the effect of hypoxia via a HIF-FOXO1 pathway that produces metabolic reprogramming and development of insulin resistance in fetal sheep hepatocytes. To test this proposed pathway, isolated hepatocytes from normal and PI-IUGR fetal sheep will be exposed to normoxic and hypoxic conditions. The expression of genes in gluconeogenesis, glycolysis, and glucose oxidation and other HIF and FOXO1 target genes will be measured to assess the effect of hypoxia on the induction of metabolic reprogramming. Glucose production rates with and without insulin will be measured to assess insulin sensitivity. FOXO1 activation and localization will be measured to determine the effect of hypoxia and insulin sensitivity. Gene silencing will be used to test the role of FOXO1. Overall, these results will demonstrate whether a novel mechanism between HIF and FOXO1 contributes to changes in fetal hepatic glucose metabolism and insulin resistance resulting from chronic hypoxia during PI-IUGR. These results will have significant scientific and potential clinical impact because IUGR affects up to 6-10% of pregnancies, yet it remains unclear how IUGR offspring develop increased risk for metabolic disease in later life. A link between early exposure to hypoxia, along with other nutrient deficiencies, during PI-IUGR and increased hepatocellular nuclear FOXO1 activity during fetal life may hold the key to understanding how PI-IUGR promotes the development of hepatic insulin resistance and dysregulated hepatic glucose production, which underlie later life development of T2DM. Overall, these new R03 studies combined with our K01 results will provide a detailed framework describing the coordinated changes in hepatic metabolism that develop in utero during PI- IUGR and predispose the liver to metabolic problems after birth.

Public Health Relevance

The proposed research is relevant to public health because IUGR is a significant cause of increased fetal and neonatal mortality and morbidity. IUGR also has a major effect on the developing fetal liver and persistent effects across the lifespan on development of metabolic diseases. By understanding the early fetal mechanisms, these studies will be fundamental to developing novel strategies aimed at understanding and reversing such adverse conditions before they contribute to later life diseases, including increased hepatic glucose production and hepatic insulin resistance, both hallmarks of type 2 diabetes, in IUGR offspring.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Small Research Grants (R03)
Project #
Application #
Study Section
Digestive Diseases and Nutrition C Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Colorado Denver
Schools of Medicine
United States
Zip Code
Boehmer, B H; Brown, L D; Wesolowski, S R et al. (2018) Pulsatile hyperglycemia increases insulin secretion but not pancreatic ?-cell mass in intrauterine growth-restricted fetal sheep. J Dev Orig Health Dis 9:492-499
Soto, Susan M; Blake, Amy C; Wesolowski, Stephanie R et al. (2017) Myoblast replication is reduced in the IUGR fetus despite maintained proliferative capacity in vitro. J Endocrinol 232:475-491
Brown, Laura D; Kohn, Jaden R; Rozance, Paul J et al. (2017) Exogenous amino acids suppress glucose oxidation and potentiate hepatic glucose production in late gestation fetal sheep. Am J Physiol Regul Integr Comp Physiol 312:R654-R663
Benjamin, Joshua S; Culpepper, Christine B; Brown, Laura D et al. (2017) Chronic anemic hypoxemia attenuates glucose-stimulated insulin secretion in fetal sheep. Am J Physiol Regul Integr Comp Physiol 312:R492-R500
Wesolowski, Stephanie R; Kasmi, Karim C El; Jonscher, Karen R et al. (2017) Developmental origins of NAFLD: a womb with a clue. Nat Rev Gastroenterol Hepatol 14:81-96
Hay Jr, William W; Brown, Laura D; Rozance, Paul J et al. (2016) Challenges in nourishing the intrauterine growth-restricted foetus - Lessons learned from studies in the intrauterine growth-restricted foetal sheep. Acta Paediatr 105:881-9
Culpepper, Christine; Wesolowski, Stephanie R; Benjamin, Joshua et al. (2016) Chronic anemic hypoxemia increases plasma glucagon and hepatic PCK1 mRNA in late-gestation fetal sheep. Am J Physiol Regul Integr Comp Physiol 311:R200-8
Brown, Laura D; Wesolowski, Stephanie R; Kailey, Jenai et al. (2016) Chronic Hyperinsulinemia Increases Myoblast Proliferation in Fetal Sheep Skeletal Muscle. Endocrinology 157:2447-60
Wesolowski, Stephanie R; Hay Jr, William W (2016) Role of placental insufficiency and intrauterine growth restriction on the activation of fetal hepatic glucose production. Mol Cell Endocrinol 435:61-68
Brown, Laura D; Davis, Melissa; Wai, Sandra et al. (2016) Chronically Increased Amino Acids Improve Insulin Secretion, Pancreatic Vascularity, and Islet Size in Growth-Restricted Fetal Sheep. Endocrinology 157:3788-3799

Showing the most recent 10 out of 14 publications