Sustained hypoxemia in late gestation potentiates hepatic gluconeogenic gene expression but does not activate glucose production in the ovine fetus

Abstract

Fetal hypoxemia is associated with pregnancy conditions that cause an early activation of fetal glucose production. However, the independent role of hypoxemia to activate this pathway is not well understood. We hypothesized that fetal hypoxemia would activate fetal glucose production by decreasing umbilical glucose uptake and increasing counter-regulatory hormone concentrations. We induced hypoxemia for 9 days with maternal tracheal N2 gas insufflation to reduce maternal and fetal arterial Po2 by ~20% (HOX) compared with fetuses from ewes receiving intratracheal compressed air (CON). At 0.9 of gestation, fetal metabolic studies were performed ( n = 7 CON, 11 HOX). Umbilical blood flow rates, net fetal oxygen and glucose uptake rates, and fetal arterial plasma glucose concentrations were not different between the two groups. Fetal glucose utilization rates were lower in HOX versus CON fetuses but not different from umbilical glucose uptake rates, demonstrating the absence of endogenous glucose production. In liver tissue, mRNA expression of gluconeogenic genes G6PC (P < 0.01) and PCK1 ( P = 0.06) were six- and threefold greater in HOX fetuses versus CON fetuses. Increased fetal norepinephrine and cortisol concentrations and hepatic G6PC and PCK1 expression were inversely related to fetal arterial Po2. These findings support a role for fetal hypoxemia to act with counter-regulatory hormones to potentiate fetal hepatic gluconeogenic gene expression. However, in the absence of decreased net fetal glucose uptake rates and plasma glucose concentrations, hypoxemia-induced gluconeogenic gene activation is not sufficient to activate fetal glucose production.

Late gestation fetal hyperglucagonaemia impairs placental function and results in diminished fetal protein accretion and decreased fetal growth

“…To quantify the metabolic actions of glucagon in the developing fetus, an established experimental model was utilized to study placental nutrient transfer, fetal nutrient metabolism, and fetal growth in chronically catheterized late gestation fetal lambs (Meschia et al 1965;Hay et al 1981;Regnault et al 2003;Rozance et al 2006;Barry et al 2008;Maliszewski et al 2012;Gadhia et al 2013;Brown et al 2016a;Wai et al 2018;Jones et al 2019). The overall study design is depicted in Fig.…”

“…After baseline lab draws on the final infusion day, all fetuses were given a primed (30 μmol/kg) continuous infusion with l-[1-13 C]leucine (∼0.5 μmol/min/kg estimated fetal weight; Cambridge Isotope Laboratories, Tewksbury, MA, USA) via fetal inferior vena cava catheter to measure fetal leucine metabolism (Carver et al 1997;Brown et al 2012Brown et al , 2016bMaliszewski et al 2012;Wai et al 2018). After 90 min, a primed (5 μCi/kg) continuous infusion of 3 H 2 O (0.5 μCi/min; PerkinElmer, Waltham, MA, USA) was added to measure uterine and umbilical blood flow via the steady state transplacental diffusion technique (Meschia et al 1980;Battaglia & Meschia, 1986c;Carver et al 1997;Rozance et al 2009;Brown et al 2012;Jones et al 2019). Simultaneously, a primed continuous infusion of [U-14 C]glucose was provided to measure fetal glucose metabolism.…”

“…After isotopic steady state was achieved (180 min for leucine tracer, 90 min for tritiated water and glucose tracers), blood was simultaneously sampled from α, γ , A and V catheters (4.5 ml from each) every 15 min for a total of four draws for plasma analysis of glucose, lactate, amino acids, KIC, and stable isotopic enrichments of [1-13 C] leucine and [1-13 C] KIC, and whole blood 13 CO 2 , 3 H 2 O and blood gas. During this period, fetuses also received an isovolumic transfusion of maternal blood to replace fetal blood sampled and prevent hypovolaemia and acute anaemia (Carver et al 1997;Brown et al 2012Brown et al , 2016bMaliszewski et al 2012;Jones et al 2019). Immediately following the fourth steady state blood draw, fetuses were subjected to a hyperglycaemic clamp study to measure fetal insulin secretion (Gadhia et al 2013).…”

Gestational Hypoxia and Programing of Lung Metabolism

“…Epigenetic changes can result in modifications in DNA methylation, histone modifications, as well as changes in non-coding RNAs all of which regulate gene transcription and translation allowing for developmental plasticity (Ducsay et al, 2018). Associated with these epigenetic modifications, short term sojourns to high altitude can induce developmental adaptations as well as abnormalities (Jones et al, 2019). While we do not know all of the changes in the pulmonary vasculature due to prenatal hypoxic exposure and high altitude living, the genetic and epigenetic changes due to high altitude living are likely to have great impact on cellular metabolism (Woolcott et al, 2015; Murray, 2016; Murray and Horscroft, 2016; Stenmark et al, 2018).…”

“…Long-term residence at high altitude in comparison may lower a person’s glycemic index and improve glucose uptake and utilization (Woolcott et al, 2015). Recent work in the sheep fetus exposed to gestational hypoxia for 9 days may provide some insight as the data shows there is an increase in hepatic expression of G6PC and PCK1 without any change in plasma glucose (Jones et al, 2019). Overall, the relationships between ROS, cellular metabolism, and the functional consequences remain to be elucidated in humans and animal models.…”