Consequences of early nutritional insults on fetal hepatic glucose metabolism and insulin action

Abstract Text: Pregnancies complicated by placental insufficiency or reduced maternal nutrient supply produce fetuses with intrauterine growth restriction (IUGR).  These in utero insults expose the fetus to a reduced supply of glucose, amino acids, and, in some cases, oxygen.  The fetus adapts to these reductions in nutrient supply by reducing insulin secretion, increasing counter-regulatory hormone levels, and developing coordinated tissue-specific adaptations in glucose metabolism. Data from our fetal sheep model of IUGR demonstrate an early activation of hepatic glucose production and increased hepatic gluconeogenic gene expression (PCK1, G6PC) that are sustained during a hyperinsulinemic-euglycemic clamp, thus demonstrating the development of hepatic insulin resistance. This is liver specific insulin resistance because the IUGR fetus has a robust increase in non-hepatic insulin-stimulated glucose utilization in peripheral tissues. While, this early activation of glucose production in utero may be an important adaptive response to produce glucose for other glucose-consuming fetal tissues, uncontrolled and dysregulated hepatic glucose production has adverse consequences postnatally and is a major component to diabetes in humans. The early mechanisms driving dysregulated hepatic glucose production and insulin resistance in the fetal liver are not fully understood. We have found that the AKT protein is robustly phosphorylated in the IUGR liver in response to insulin, yet downstream FOXO1 phosphorylation and nuclear localization is increased. We also find that despite decreased nutrient supply, stress signals like AMPK are not increased in the IUGR fetal liver. In addition to increased glucose production, our recent data also demonstrate decreased mitochondrial oxidation in the IUGR fetal liver and a compensatory increase in hepatic glycolysis, intrahepatic lactate production and utilization, and altered substrate preference for reduced hepatic oxidative metabolism. This combination of metabolic adaptations by the fetal liver may be necessary to activate and sustain GPR. However, decreased hepatic mitochondrial function that persists postnatally may underlie the development of hepatic steatosis in offspring who were IUGR. Overall, understanding the endocrine and molecular pathways responsible for these early metabolic adaptations in the fetus, will allow for development of targeted strategies to improve liver function in the fetus and improve postnatal growth and performance and decrease risk for diabetes and metabolic disease later in life.

Keywords: metabolic adaptations, fetus, nutrition