Impact of maternal overnutrition on gluconeogenic factors and methylation of the phosphoenolpyruvate carboxykinase promoter in the fetal and postnatal liver.
BACKGROUND
Exposure to maternal obesity or hyperglycemia increases the risk of obesity and poor glucose tolerance in the offspring. We hypothesized that maternal overnutrition in late pregnancy would result in (i) lower methylation in the promoter region of the cytosolic form of phosphoenolpyruvate carboxykinase (PEPCK-C; PCK1) and (ii) higher expression of hepatic gluconeogenic factors in the fetal and postnatal lamb.


METHODS
Ewes were fed 100% (n = 18) or ~155% (n = 17) of energy requirements from 115 d gestation, and livers were collected at ~140 d gestation or 30 d postnatal age.


RESULTS
Maternal overnutrition resulted in a decrease in hepatic expression of the mitochondrial form of PEPCK (PEPCK-M; PCK2) but not of PEPCK-C or glucose-6-phosphatase (G6PHOS) before and after birth. Hepatic expression of peroxisome proliferator-activated receptor γ coactivator 1 (PGC-1), peroxisome proliferator-activated receptor α (PPARα), PEPCK-C, G6PHOS, and 11β hydroxysteroid dehydrogenase type 1 (11βHSD1), but not PEPCK-M, was higher in the postnatal lamb compared with that in the fetal lamb. The level of PCK1 methylation was paradoxically approximately twofold higher in the postnatal liver compared with that in the fetal liver.


CONCLUSIONS
Maternal overnutrition programs a decrease in hepatic PEPCK-M in the offspring and as ~50% of total hepatic PEPCK is PEPCK-M, the longer-term consequences of this decrease may be significant.
1] School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia [2] Discipline of Physiology, School of Molecular and Biomedical Science, University of Adelaide, Adelaide, South Australia, Australia.
Leewen
L
Rattanatray
School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.
Beverly S
BS
Muhlhausler
School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.
Lisa M
LM
Nicholas
School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.
Janna L
JL
Morrison
School of Pharmacy and Medical Sciences, Sansom Institute for Health Research, University of South Australia, Adelaide, South Australia, Australia.
I Caroline
IC
McMillen
D000818:Animals; D019175:DNA Methylation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D005943:Gluconeogenesis / Q000235:genetics; D008099:Liver / Q000196:embryology / Q000201:enzymology / Q000378:metabolism*; D044343:Overnutrition; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000235:genetics*; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D012756:Sheep / Q000196:embryology / Q000254:growth & development
D019764:Phosphoenolpyruvate Carboxykinase (ATP)