Background IUGR predisposes towards long-term morbidities such as insulin resistance. Corticosterone regulates hepatic gluconeogenesis. The glucocorticoid receptor (GR) and its phosphorylation (S211) status, and 11 beta hydroxysteroid dehydrogenase (11β-HSD 1) are key components of the steroid metabolism.
Hypothesis We hypothesized that IUGR and subsequent paracrine glucocorticoid overexposure of the fetus would lead to short and long-term alterations in the steroid metabolism key components.
Methods Bilateral uterine artery ligation was performed on d19 pregnant Sprague-Dawley rats and pups were harvested at term. Plasma corticosterone levels (CORT) were measured at d0 and d21 by ELISA. Hepatic GR and 11 β-HSD 1 mRNA levels were quantified using real time-PCR. Protein levels of GR, 11 β-HSD 1 and serine 211 (S211) were measured by Western blot.
Results On d0, CORT and mRNA GR increased in IUGR pups, but 11 β-HSD 1mRNA decreased. On d21, CORT remained elevated in IUGR rats, with decreased mRNA GR and 11 β-HSD 1in IUGR females. (Table)
On d0, there was increased hepatic GR (S211) phosphorylation in IUGR rats (162±10 % of control values, p≤0.01). However, we found decreased S211 levels in d21 IUGR males (40±3 % of control values, p≤0.001), with preservation of GR phosphorylation in IUGR females (104±%of control values, NS).
Conclusion Uteroplacental insufficiency is associated with prenatal and postnatal glucocorticoid overexposure that most likely affects steroid metabolism in a time and gender-specific manner. We speculate that increased glucocorticoid levels at day 0 and day 21 may contribute to the molecular mechanisms underlying insulin resistance in adulthood.