title: Intrauterine growth restriction and differential patterns of hepatic growth and expression of IGF1, PCK2, and HSDL1 mRNA in the sheep fetus in late gestation.
abstract: Fetal adaptations to periods of substrate deprivation can result in the programming of glucose intolerance, insulin resistance, and metabolic dysfunction in later life. Placental insufficiency can be associated with either sparing or sacrifice of fetal liver growth, and these different responses may have different metabolic consequences. It is unclear what intrahepatic mechanisms determine the differential responses of the fetal liver to substrate restriction. We investigated the effects of placental restriction (PR) on liver growth and the hepatic expression of SLC2A1, IGF1, IGF2, IGF1R, IGF2R, PPARGC1A, PPARA, PRKAA1, PRKAA2, PCK2, and HSDL1 mRNA in fetal sheep at 140-145 days of gestation. A mean gestational arterial partial pressure of oxygen less than 17 mmHg was defined as hypoxic, and a relative liver of weight more than 2 SD below the mean liver weight of controls was defined as reduced liver growth. Fetuses therefore were defined as control-normoxic (C-N; n = 9), PR-normoxic (PR-N; n = 7), PR-hypoxic (PR-H; n = 8), or PR-hypoxic reduced liver growth (PR-H RLG; n = 4). Hepatic SLC2A1 mRNA expression was highest (P < 0.05) in the PR-H fetuses, in which liver growth was maintained. Expression of IGF1 mRNA was decreased (P < 0.05) only in the PR-H RLG group. Hepatic expression of HSDL1, PPARGC1A, and PCK2 mRNA also were increased (P < 0.05) in the PR-H RLG fetuses. The present study highlights that intrahepatic responses to fetal substrate restriction may exist that protect the liver from decreased growth and, potentially, from a decreased responsiveness to the actions of insulin in postnatal life.
authors.affiliation: Early Origins of Adult Health Research Group, Sansom Institute, School of Pharmacy and Medical Sciences, University of South Australia, South Australia, Australia. Sheridan.Gentili@unisa.edu.au
authors.forename: Sheridan
authors.initials: S
authors.lastname: Gentili
authors.forename: Janna L
authors.initials: JL
authors.lastname: Morrison
authors.forename: I Caroline
authors.initials: IC
authors.lastname: McMillen
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism*; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism*; D005311:Fetal Hypoxia / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D005993:Glycerolphosphate Dehydrogenase / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D008099:Liver / Q000254:growth & development* / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D012756:Sheep; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D051272:Glucose Transporter Type 1; D047493:PPAR alpha; D012333:RNA, Messenger; D017527:Receptor, IGF Type 2; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D005993:Glycerolphosphate Dehydrogenase; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D017526:Receptor, IGF Type 1; D055372:AMP-Activated Protein Kinases; D010729:Phosphoenolpyruvate Carboxykinase (GTP)