Maternal Undernutrition during Early to Midgestation Programs Tissue-Specific Alterations in the Expression of the Glucocorticoid Receptor, 11β-Hydroxysteroid Dehydrogenase Isoforms, and Type 1 Angiotensin II Receptor in Neonatal Sheep*

Abstract

We have investigated the effects of maternal nutrient restriction in the sheep during the period of rapid placental growth (i.e. 28-77 days gestation; term = 147 days) on feto-placental growth and expression of the glucocorticoid receptor (GR), types 1 and 2 11beta-hydroxysteroid dehydrogenase (11betaHSD1, 11betaHSD2), and types 1 and 2 angiotensin II receptor (AT1, AT2) in fetal and neonatal offspring. Ewes (n = 63) of similar age, body weight, and body composition were randomly allocated to a nutrient-restricted (NR) group in which they consumed 3.2 MJ/day metabolizable energy (ME; equivalent to 50% of predicted requirements) or to a control group in which they consumed 6.7 MJ/day ME (equivalent to 110% of predicted requirements). After 77 days gestation, ewes from both dietary groups consumed close to 100% of ME requirements up to term. Newborn offspring of NR ewes were of similar body weight, but had increased crown-rump length, greater placental weight, and increased placental/body weight ratio (P < 0.01) compared with controls. Their kidneys were heavier (P < 0.05), but shorter in length, with increased ratios of transverse width to length (P < 0.001). GR messenger RNA (mRNA) expression in neonatal offspring from NR ewes was increased in adrenal, kidney, liver, lung, and perirenal adipose tissue (P < 0.01). Conversely, 11betaHSD1 mRNA expression was unaffected, except in perirenal adipose tissue, where it was higher in lambs born to NR ewes (P < 0.01). 11betaHSD2 mRNA expression was decreased in adrenals and kidney (P < 0.001). Maternal NR also resulted in significantly increased AT1 expression in those tissues in which expression of GR was increased and/or 11betaHSD2 was decreased, i.e. adrenals, kidney, liver, and lung. AT2 expression was unaffected by maternal NR. Although 11betaHSD2 mRNA was undetectable in term placenta, it was abundant in midgestation placenta and was lower after maternal NR (P < 0.001). There was close agreement between levels of 11betaHSD enzyme (i.e. 11beta-dehydrogenase and 11-oxoreductase) activities and abundance of 11betaHSD1 mRNA and 11betaHSD2 mRNA expression. The persistence of tissue-specific increases in the expression of GR, 11betaHSD1 and AT1 and decreases in the expression of 11betaHSD2 in adrenals and kidney in newborn offspring in response to a defined period of maternal nutrient restriction during early to midgestation suggests that gene expression has been programmed by nutrient availability to the fetus before birth. These data suggest key potential mechanisms by which maternal nutrition prenatally programs physiological pathways, such as the renin-angiotensin system, in the offspring that may lead to raised blood pressure and other cardiovascular disease risk factors in later life.

Feeding pregnant rats a low-protein diet alters the hepatic expression of SREBP-1c in their offspring via a glucocorticoid-related mechanism

“…Previous work found that maternal protein restriction leads to down-regulation of 11b-hydroxysteroid dehydrogenase-2 in placenta and consequently, increased foetal exposure to maternal glucocorticoids [19,20,25,26]. This has been proposed to underlie the effects of low-protein diet on offspring phenotypes such as development of hypertension [20,23].…”

Maternal dexamethasone administration and the maturation of perirenal adipose tissue of the neonatal sheep

“…These findings indicate the sensitivity of both UCP1 and 2 to glucocorticoid status around the time of birth. 12,35 The extent to which a change in local cortisol synthesis via the enzyme 11βHSD1, which is predicted to be enhanced, 36 rather than direct stimulation of the GR receptor that is one potential stimulus for the rise in UCP remains to be clarified. With regard to the more immediate effects of maternal dexamethasone administration on fetal adipose tissue maturation, it was only gene expression for UCP2 that was raised prior to the onset of breathing.…”

Mechanisms underlying the role of glucocorticoids in the early life programming of adult disease

“…Moreover, in utero exposure to dexamethasone causes a marked increase in GR expression and attenuated fatty acid uptake in adult rats, selectively in visceral adipose tissue, which may contribute to both adipose and hepatic insulin resistance [81]. Maternal nutrient restriction during pregnancy has also been associated with increased adipose tissue GR expression and obesity in sheep [90][91][92].…”