Placental 11β-hydroxysteroid dehydrogenase-2 (11β-HSD2) rapidly converts glucocorticoids to inactive metabolites, thus protecting the developing fetus from high maternal glucocorticoids. Genetic deficiency or inhibition of 11β-HSD2 associates with fetal growth restriction, low birth weight, and cardiometabolic disease in adulthood. Similar programming effects are seen with maternal malnutrition or stress; these challenges associate with reduced placental 11β-HSD2 at term. We therefore explored the importance of 11β-HSD2 in dietary programming.
Feeding C57Bl/6J mice an isocaloric low protein (LP) diet throughout gestation (8% protein versus 18% control diet) significantly decreased placental weight (P<0.001) and fetal weight at embryonic day (E) 17.5 (0.89±0.05 g in control versus 0.74±0.03 g in low protein; P<0.001). This reduction in fetal weight was preceded by a downregulation of 11β-HSD2 enzyme activity from E16.5 (decreased in LP by 28 and 20% at E16.5 and 17.5, respectively; P<0.05). However, at earlier gestational ages (E13.515.5), LP diet increased placental 11β-HSD2 activity (increased in LP by 21, 23 and 41% at E13.5, 14.5 and 15.5, respectively; P<0.05), perhaps to maximise midgestation fetal growth. Using a heterozygous 11β-HSD2+/− mating strategy to generate 11β-HSD2+/+, +/− and −/− offspring within the same litters, maternal LP diet reduced fetal body weight to a similar extent in all genotypes compared with control offspring, although the magnitude was blunted in 11β-HSD2−/− offspring. Thus, LP diet has effects over-and-above 11β-HSD2 inhibition to reduce fetal weight gain.