TY - JOUR
T1 - Reconciling the nutritional and glucocorticoid hypotheses of fetal programming
AU - Cottrell, Elizabeth C.
AU - Holmes, Megan C.
AU - Livingstone, Dawn E.
AU - Kenyon, Christopher J.
AU - Seckl, Jonathan R.
PY - 2012/5
Y1 - 2012/5
N2 - 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). www.fasebj.org
AB - 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). www.fasebj.org
KW - low-protein diet
KW - 11β-hydroxysteroid dehydrogenase-2
KW - hypothalamo-pituitary-adrenal axis
UR - http://www.scopus.com/inward/record.url?scp=84860904832&partnerID=8YFLogxK
U2 - 10.1096/fj.12-203489
DO - 10.1096/fj.12-203489
M3 - Article
C2 - 22321728
VL - 26
SP - 1866
EP - 1874
JO - The FASEB Journal
JF - The FASEB Journal
SN - 0892-6638
IS - 5
ER -