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 similar to 155% (n = 17) of energy requirements from 115 d gestation, and livers were collected at similar to 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 gamma coactivator 1 (PGC-1), peroxisome proliferator-activated receptor alpha (PPAR alpha), PEPCK-C, G6PHOS, and 11 beta hydroxysteroid dehydrogenase type 1 (11 beta HSD1), 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. CONCLUSION: Maternal overnutrition programs a decrease in hepatic PEPCK-M in the offspring and as similar to 50% of total hepatic PEPCK is PEPCK-M, the longer-term consequences of this decrease may be significant.