Reconciling the nutritional and glucocorticoid hypotheses of fetal programming

Elizabeth C. Cottrell, Megan C. Holmes, Dawn E. Livingstone, Christopher J. Kenyon, Jonathan R. Seckl

Research output: Contribution to journalArticlepeer-review


Fetal growth restriction associates with increased risk of adult cardiometabolic and neuropsychiatric disorders. Both maternal malnutrition [notably a low-protein (LP) diet] and stress/glucocorticoid exposure reduce fetal growth and cause persisting abnormalities (programming) in adult offspring. Deficiency of placental 11 beta-hydroxysteroid dehydrogenase-2 (11 beta-HSD2), which inactivates glucocorticoids, is reduced by an LP diet and has been proposed as a unifying mechanism. Here, we explored the importance of glucocorticoids and placental 11 beta-HSD2 in dietary programming. Pregnant mice were fed a control or isocaloric LP diet throughout gestation. The LP diet first elevated fetal glucocorticoid levels, then reduced placental growth, and finally decreased fetal weight near term by 17%. Whereas the LP diet reduced placental 11 beta-HSD2 activity near term by similar to 25%, consistent with previous reports, activity was increased between 20 and 40% at earlier ages, implying that glucocorticoid overexposure in LP fetuses occurs via 11 beta-HSD2-independent mechanisms. Consistent with this, heterozygous 11 beta-HSD2(+/-) crosses showed that although both LP and 11 beta-HSD2 deficiency reduced fetal growth, LP indeed acted independently of 11 beta-HSD2. Instead, the LP diet induced the fetal hypothalamic-pituitary-adrenal axis per se. Thus, maternal malnutrition and placental 11 beta-HSD2 deficiency act via distinct processes to retard fetal growth, both involving fetoplacental overexposure to glucocorticoids but from distinct sources.-Cottrell, E. C., Holmes, M. C., Livingstone, D. E., Keynon, C. J., Seckl, J. R. Reconciling the nutritional and glucocorticoid hypotheses of fetal programming. FASEB J. 26, 1866-1874 (2012).

Original languageEnglish
Pages (from-to)1866-1874
Number of pages9
JournalThe FASEB Journal
Issue number5
Publication statusPublished - May 2012


  • low-protein diet
  • 11β-hydroxysteroid dehydrogenase-2
  • hypothalamo-pituitary-adrenal axis


Dive into the research topics of 'Reconciling the nutritional and glucocorticoid hypotheses of fetal programming'. Together they form a unique fingerprint.

Cite this