Effect of uteroplacental insufficiency upon brain neuropeptide Y and corticotropin-releasing factor gene expression and concentrations.

Abstract

Various hypothalamic functions such as feeding behavior, energy expenditure, body weight gain, level of anxiety, and sexual maturation are mediated by a balance between the concentrations of neuropeptide Y (NPY) and corticotropin-releasing factor (CRF). To test the hypothesis that maternal uteroplacental insufficiency alters the offspring's brain NPY and/or CRF levels, we examined the effect of maternal uterine artery ligation with intrauterine growth restriction (IUGR) (p < 0.05) upon fetal (20 d) and postnatal (4, 14, and 21 d) brain NPY and CRF synthesis, concentrations, and regional distribution. An age-related increase in NPY (0.8 kb) and CRF (1.4 kb) mRNA levels with peak amounts at the 14-d postnatal age (p < 0.05) was observed. IUGR was associated with a 75% increase in fetal brain NPY mRNA levels (p < 0.05) with no change in NPY peptide, CRF mRNA and peptide amounts. Although the increase in NPY mRNA levels persisted postnatally (p < 0.05) at d 4 and 21, CRF mRNA amounts were 2.5-fold higher only in the 4-d IUGR (p < 0.05). Paralleling the mRNA changes, an age-related increase in RIA of NPY and CRF peptide concentrations was noted (p < 0.05). IUGR caused postnatal brain NPY and CRF peptide changes similar to corresponding mRNA levels (p < 0.05), despite normal postnatal circulating glucose, insulin, corticosterone, and leptin concentrations. The age-specific intergroup differences in the NPY and CRF peptide immunoreactivity appeared predominantly in the hypothalamic region. We conclude that maternal uteroplacental insufficiency causing IUGR leads to a pretranslational imbalance in the immediate (4 d) postnatal brain NPY and CRF peptide concentrations, thereby altering the developmental pattern. This alteration in NPY and CRF peptide concentrations, despite normalization of the metabolic milieu was associated with a persistent diminution in body weight. The IUGR-associated pretranslational increase in NPY and not CRF peptide levels at d 21, may herald changes in feeding behavior during the postsuckling phase.