Ontogeny and nutritional manipulation of the hepatic prolactin–growth hormone–insulin-like growth factor axis in the ovine fetus and in neonate and juvenile sheep

Abstract

The somatotrophic axis is the main endocrine system regulating postnatal growth; however, prenatal growth is independent of growth hormone (GH). Fetal development relies on the coordinated actions of a range of hormones, including insulin-like growth factors (IGF), and prolactin (PRL), in the control of differentiation, growth and maturation. In the sheep the abundance peaks for liver IGF-II and PRL receptors occur during late gestation while that for IGF-I receptor occurs at birth. All receptors, with the exception of GH receptor subsequently decrease by age 6 months. It has been proposed that maternal undernutrition during gestation regulates the maturation of the fetal hypothalmic-pituitary-adrenal axis and endocrine sensitivity. Critically, the timing of the nutritional insult may affect the magnitude of reprogramming. Maternal malnutrition during early to mid-gestation (3 . 2-3 . 8 MJ/d (60 % total metabolisable energy requirements) v. 8 . 7-9 . 9 MJ/d (150 % total metabolisable energy requirements) between 28 and 80 d of gestation) had no effect on body or liver weight. Nutrient-restricted (NR) fetuses sampled at 80 d (mid-gestation) showed up-regulation of hepatic PRL receptor, but following refeeding the normal gestational rise in PRL and GH receptors did not occur. Hepatic IGF-II receptor was down regulated in NR fetuses at both midand late gestation. Conversely, 6-month-old offspring showed no difference in the abundance of either GH receptor or PRL receptor, while IGF-II mRNA was increased. Offspring of ewes malnourished during late gestation (9 . 1 MJ/d (60 % total metabolisable energy requirements) v. 12 . 7 MJ/d (100 % total metabolisable energy requirements) from 110 d of gestation to term) showed reduced abundance of hepatic GH and PRL receptor mRNA. In conclusion, maternal undernutrition during the various stages of gestation reprogrammed the PRL-GH-IGF axis.

Endocrine And Metabolic Adaptations Of Calves To Extra-Uterine Life

“…Fetal IGF-I synthesis is not under control of GH, as it is in the adult animal [57]. GH may be detected in ovine fetal circulation as early as day 130 of gestation, but its origin is still unknown since there is no precise evidence that fetal adenohypophysis may synthetise GH [62]. Abundance of IGFBPs in the fetal circulation differs from adult animals.…”

Extracellular signal-regulated kinases (ERK1/2) signaling pathway plays a role in cortisol secretion in the long-term hypoxic ovine fetal adrenal near term

“…Surprisingly, we noted robust basal phosphorylation of both ERK1 and ERK2 in both LTH and control FACs, perhaps reflecting the mitotically active nature of the FACs. Elevated levels of growth factors observed during development (1,20,26) or NH 2 -terminal POMC-derived peptides may contribute to the enhanced level of phosphorylation. In response to UO126 inhibition of ERK1/2 we noted a profound inhibitory effect on both ACTH and 8-bromo-cAMP stimulated cortisol biosynthesis in both groups, virtually eliminating the ability to produce cortisol in response to ACTH and cAMP in control FACs while severely blunting the response in the LTH FAC.…”

Maternal nutrient restriction in early pregnancy programs hepatic mRNA expression of growth-related genes and liver size in adult male sheep

“…Gluconeogenesis is regulated by glucocorticoids and GH as well as catecholamines and insulin (Cherrington 1999), and there is good evidence that fetal hepatic sensitivity to both cortisol (Whorwood et al 2001) and GH , Hyatt et al 2004 can be programmed in utero. In the present study, there was a statistical trend for NR offspring to exhibit increased GR mRNA abundance despite no difference in plasma cortisol (Gopalakrishnan et al 2004) or 11bHSD types 1 and 2 mRNA, which is therefore likely to be reflected in similar hepatic enzyme activities between groups (Whorwood et al 2001).…”

“…Hepatic IGF-IR mRNA levels were undetectable in adult sheep, irrespective of prenatal nutrition. Expression of IGF-IR in liver tissue normally decreases with postnatal age (Hyatt et al 2004) and tissue maturation. Hepatic IGF-II expression was similarly unaffected by prenatal nutrition.…”

“…This includes the onset of hepatic gluconeogenesis (Gardner et al 2001, Forhead et al 2003 in conjunction with an increase in mRNA abundance of a number of genes that can potentially regulate liver function including IGF-I, IGF-II (Forhead et al 2000), and prolactin receptors (PRLR; Hyatt et al 2004). Activation of these receptors subsequently regulates a range of cell signaling pathways, including JAK/Stat (Harding et al 2000), the negative feedback loop initiated from changes in abundance of suppressor of cytokine signaling (SOCS) molecules (Ram & Waxman 1999).…”