Effects of Maternal Global Nutrient Restriction on Fetal Baboon Hepatic Insulin-Like Growth Factor System Genes and Gene Products

Abstract

Knowledge of altered maternal nutrition effects on growth-regulating systems is critical to understanding normal and abnormal fetal development. There are many reports of hepatic fetal IGF system responses to maternal nutrient restriction (MNR) during pregnancy in rodents and sheep but none in nonhuman primates. We determined effects of MNR on the fetal baboon hepatic IGF system. Social groups of female baboons were fed ad libitum, controls, or 70% controls (MNR) from 0.16 to 0.5 gestation and fetuses delivered by cesarean section. Fetal liver tissue was analyzed for IGF-I, IGF-II, and IGF binding protein (IGFBP)-3 mRNA by in situ hybridization and quantitative RT-PCR and protein by immunohistochemistry (IHC); IGF-I receptor, IGF-II receptor by quantitative RT-PCR and IHC and IGFBP-1 by in situ hybridization and IHC. MNR did not alter fetal body or liver weight. Fetal hepatic glycogen staining increased with MNR. MNR reduced fetal hepatic IGF-I and IGF-II and increased IGFBP-1 mRNA and decreased IGF-I, IGF-II, IGF-I receptor, and IGF-II receptor protein and increased protein for IGFBP-1 and IGFBP-3. MNR increased caspase-3, indicating apoptosis and decreased Akt staining, indicating decreased nutrient sensing. In conclusion, whereas fetal body and liver weights did not change in response to moderate MNR during the first half of baboon pregnancy, the major indices of function of the hepatic IGF system measured were all reduced.

Influence of moderate maternal nutrition restriction on the fetal baboon metabolome at 0.5 and 0.9 gestation

“…In baboons, moderate maternal nutrition restriction (MNR) has only minor effects on overall fetal growth at 0.5 gestation (G -term 184 days) [7,8], but at 0.9G fetuses show intrauterine growth restriction [9]. Decreased maternal nutrition in pregnant baboons was shown to alter the placental nutrient transfer [10], fetal metabolism [7] and was associated with an increased risk for postnatal adverse outcomes such as insulin resistance [11]. Metabolic adaptations during development in response to decreased fetal nutrition may persist after birth, even when nutrition has returned to the normal range [12].…”

Identification and comparative analyses of myocardial miRNAs involved in the fetal response to maternal obesity

“…Two recent studies have identified and profiled baboon liver miRNAs that are responsive to dietary fat and cholesterol (56). We and others have studied maternal and fetal baboon physiology in both normal pregnancy and following perturbations that led to developmental programming (65). We have shown that maternal overnutrition in sheep leads to impaired fetal cardiac function and altered insulin signaling (104).…”

Moderate Global Reduction in Maternal Nutrition Has Differential Stage of Gestation Specific Effects on β1- and β2-Adrenergic Receptors in the Fetal Baboon Liver

“…Interestingly, fetal liver glycogen as well as phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme for gluconeogenesis, is distributed similarly around the central lobular vein. 2,3 Numerous studies have suggested that one of the mechanisms by which catecholamines mobilize glucose from the liver in times of need is by stimulation of PEPCK via activation of b-ARs. 5,32,33 It is therefore plausible that localization of b-ARs, glycogen, and PEPCK around the central lobular vein is to maintain an adequate glucose status during fetal development.…”

“…Among the documented fetal hepatic responses to reduced nutrient availability in baboon pregnancy are altered functions of the insulin-like growth factor (IGF) axis including increased liver glycogen. 2 Since the fetal liver plays a central role in basal as well as perturbed fetal metabolic function, we have begun a series of studies to evaluate both normal ontogeny and responses to MNR. 2,3 Part of our rationale is the need to rectify the scarcity of information available on the ontogeny and physiological responses of fetal hepatic betaadrenergic receptors (b-ARs) to challenges such as reduced maternal nutrition.…”