title: Nutritional mismatch in postnatal life of low birth weight rat offspring leads to increased phosphorylation of hepatic eukaryotic initiation factor 2 α in adulthood.
abstract: OBJECTIVE
  Epidemiological studies have established that low birth weight offspring, when faced with a nutritional mismatch in postnatal life, have an increased risk of developing the metabolic syndrome. Our laboratory and others have demonstrated that maternal protein restriction (MPR) leads to high cholesterol and insulin resistance in the offspring due to impaired liver function, though the underlying molecular mechanisms remain elusive. Recent in vitro studies have associated decreased phosphorylation of Akt1 (Serine 473), a marker of insulin sensitivity, with increased phosphorylation of eukaryotic initiation factor (eIF)-2α (Serine 51), a key regulator of protein translation attenuation. The main aim of the study was to determine whether nutritional mismatch in MPR offspring leads to elevated phospho-eIF2α (Ser51) levels in the liver.
  
  
  METHODS
  To investigate if this occurs long-term in MPR offspring, pregnant Wistar rats were fed a control (20%) protein diet (control) or a low (8%) protein diet during pregnancy and postnatal life (LP1), or during pregnancy and lactation (LP2).
  
  
  RESULTS
  At postnatal day 130, LP2 offspring exhibited increases in hepatic phosphorylation of eIF2α (Ser51) concomitant with decreases in the phosphorylation of Akt1 (Ser473), while LP1 offspring exhibited the converse relationship. Interestingly, in embryonic day 19 livers derived from control or MPR pregnancy, no changes in eIF2α (Ser51) or Ak1 (Ser473) phosphorylation were observed.
  
  
  CONCLUSIONS
  Collectively, our data provide robust evidence that phosphorylation of eIF2α (Ser51) is inversely correlated with phosphorylated Akt1 (Ser473) in vivo. Moreover, this study demonstrates that this inverse relationship is adversely influenced in these MPR offspring by a mismatch in the postnatal nutritional environment.
authors.affiliation: The Children's Health Research Institute and the Lawson Health Research Institute, Department of Obstetrics and Gynecology and Physiology and Pharmacology, The University of Western Ontario, London, Ontario, Canada N6A 5C1.
authors.forename: Gurjeev
authors.initials: G
authors.lastname: Sohi
authors.forename: Andrew
authors.initials: A
authors.lastname: Revesz
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Hardy
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001724:Birth Weight / Q000502:physiology*; D018753:Diet, Protein-Restricted; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D005260:Female; D007333:Insulin Resistance / Q000502:physiology; D007774:Lactation / Q000378:metabolism / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D010766:Phosphorylation; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism*; D014176:Protein Biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D015852:Eukaryotic Initiation Factor-2; C494920:Akt1 protein, rat; D051057:Proto-Oncogene Proteins c-akt
keywords: C/EBP homologous protein; CHOP; CVD; Endoplasmic reticulum stress; Fetal programming; GRP78/94; Glucose regulated protein 78/94; Growth; IUGR; LP; Low protein diet; MPR; Metabolic syndrome; Predictive adaptive response hypothesis; Protein translation; RT; Thrifty phenotype; X-box binding protein 1; Xbp1; cDNA; cardiovascular disease; copy DNA; e19; eIF2α (Ser51); embryonic day 19; eukaryotic initiation factor-2α (Serine 51); intrauterine growth restriction; low protein; maternal protein restriction; reverse transcriptase