Prenatal hypoxia independent of undernutrition promotes molecular markers of insulin resistance in adult offspring

Abstract

Molecular mechanisms predisposing people to insulin resistance are starting to emerge. Altered insulin signaling for hepatic gluconeogenesis and muscle glucose uptake is thought to play a central role. Development under suboptimal conditions is also known to increase the risk of insulin resistance in adulthood. However, the partial contributions of reduced oxygen vs. nutrient delivery to the fetus, two common adverse conditions in utero, to developmental programming of insulin resistance remain unknown. The aim of this study was to determine the effects of developmental hypoxia or undernutrition on the expression of insulin-signaling proteins in liver and skeletal muscle in adult rat offspring. We show that the expression of hepatic phospho-Akt and muscle Akt2 were significantly reduced in offspring of hypoxic, relative to offspring from normoxic or undernourished, pregnancies. Hepatic Akt-1, Akt-2, and PKCζ protein expression was reduced in offspring from both hypoxic and undernourished pregnancies. Muscle GLUT4 expression was decreased in undernourished, and further decreased in hypoxic, offspring. These findings link prenatal hypoxia to down-regulation of components of hepatic and muscle Akt expression in adult offspring. Akt may represent a pharmaceutical target for clinical intervention against the developmental programming of metabolic disease resulting from prenatal hypoxia.

Effect of intrauterine growth retardation on liver and long-term metabolic risk

“…It has recently been demonstrated that the exposure to hypoxia in utero inhibits the expression of hepatic phospho-Akt-1, Akt-2 and PKCz in adult offspring. 68 It is noteworthy that maternal overfeeding may also program liver metabolism. 69 Mice offspring of dams with high fat intake during pregnancy show insulin resistance, reduced glucose transporter-2 expression and hepatic steatosis.…”

Protective Effect of N-acetylcysteine on Liver Damage During Chronic Intrauterine Hypoxia in Fetal Guinea Pig

“…20,21 Chronic hypoxia impairs carbohydrate metabolism 11 and insulin signaling 23 in the fetal sheep liver, having a programming effect on insulin resistance in the offspring. 24 We propose that fetal hypoxia is likely to have a significant impact on normal liver function in utero via oxidative stress, contributing to altered fetal growth and metabolism.…”

Gestational Hypoxia Induces Preeclampsia-Like Symptoms via Heightened Endothelin-1 Signaling in Pregnant Rats

“…The pregnancy complications with abnormal fetal development not only significantly increase maternal and infant mortality and morbidity rates, 3–6 but also have long-term adverse effects on adult health, predisposing to cardiovascular and metabolic diseases. 7–10 The hallmark of preeclampsia is a shallow trophoblast invasion and insufficient spiral artery remodeling, leading to persistent placental hypoxia and the release of various mediators into the maternal circulation resulting in preeclamptic symptoms. 1 …”