Postnatal growth velocity modulates alterations of proteins involved in metabolism and neuronal plasticity in neonatal hypothalamus in rats born with intrauterine growth restriction☆

Abstract 

Intrauterine growth restriction (IUGR) due to maternal protein restriction is associated in rats with an alteration in hypothalamic centers involved in feeding behaviour. In order to gain insight into the mechanism of perinatal maternal undernutrition in the brain, we used proteomics approach to identify hypothalamic proteins that are altered in their expression following protein restriction in utero. We used an animal model in which restriction of the protein intake of pregnant rats (8% vs. 20%) produces IUGR pups which were randomized to a nursing regimen leading to either rapid or slow catch-up growth. We identified several proteins which allowed, by multivariate analysis, a very good discrimination of the three groups according to their perinatal nutrition. These proteins were related to energy-sensing pathways (Eno 1, E₂PDH, Acot 1 and Fabp5), redox status (Bcs 1L, PrdX3 and 14-3-3 protein) or amino acid pathway (Acy1) as well as neurodevelopment (DRPs, MAP2, Snca). In addition, the differential expressions of several key proteins suggested possible shunts towards ketone-body metabolism and lipid oxidation, providing the energy and carbon skeletons necessary to lipogenesis. Our results show that maternal protein deprivation during pregnancy only (IUGR with rapid catch-up growth) or pregnancy and lactation (IUGR with slow postnatal growth) modulates numerous metabolic pathways resulting in alterations of hypothalamic energy supply. As several of these pathways are involved in signalling, it remains to be determined whether hypothalamic proteome adaptation of IUGR rats in response to different postnatal growth rates could also interfere with cerebral plasticity or neuronal maturation.

Abbreviations: IUGR, intrauterine growth retardation, PND, postnatal day, CC, control, RC, IUGR with rapid postnatal catch-up growth, RR, IUGR with slow postnatal growth, 2-DE, two-dimensional gel electrophoresis, IPG, immobilized pH gradient, SDS, sodium dodecyl sulphate, PAGE, polyacrylamide gel electrophoresis, MS, mass spectrometry, LC-MS/MS, liquid chromatography-tandem mass spectrometry, PCA, principal component analysis, PLS-DA, partial least-squares discriminant analysis, GO, Gene Ontology.

Keywords: Intrauterine growth restriction, Hypothalamus, Proteomics, Metabolism