Maternal overnutrition suppresses the phosphorylation of 5′-AMP-activated protein kinase in liver, but not skeletal muscle, in the fetal and neonatal sheep

Philp LK, Muhlhausler BS, Janovska A, Wittert GA, Duffield JA, McMillen IC. Maternal overnutrition suppresses the phosphorylation of 5'-AMP-activated protein kinase in liver, but not skeletal muscle, in the fetal and neonatal sheep. Am J Physiol Regul Integr Comp Physiol 295: R1982-R1990, 2008. First published September 10, 2008; doi:10.1152/ajpregu.90492.2008. -Epidemiological studies have shown that infants exposed to an increased supply of nutrients before birth are at increased risk of type 2 diabetes in later life. We have investigated the hypothesis that fetal overnutrition results in reduced expression and phosphorylation of the cellular fuel sensor, AMP-activated kinase (AMPK) in liver and skeletal muscle before and after birth. From 115 days gestation, ewes were fed either at or similar to 55% above maintenance energy requirements. Postmortem was performed on lamb fetuses at 139-141 days gestation (n = 14) and lambs at 30 days of postnatal age (n = 21), and liver and quadriceps muscle were collected at each time point. The expression of AMPK alpha 1 and AMPK alpha 2 mRNA was determined by quantitative RT-PCR (qRT-PCR). The abundance of AMPK alpha and phospho-AMPK alpha (P-AMPK alpha) was determined by Western blot analysis, and the proportion of the total AMPK alpha pool that was phosphorylated in each sample (% P-AMPK alpha) was determined. The ratio of AMPK alpha 2 to AMPK alpha 1 mRNA expression was lower in fetuses compared with lambs in both liver and muscle, independent of maternal nutrition. Hepatic % P-AMPK alpha was lower in both fetuses and lambs in the Overfed group and % P-AMPK alpha in the lamb liver was inversely related to plasma glucose concentrations in the first 24 h after birth (r = 0.73, P < 0.025). There was no effect of maternal overnutrition on total AMPK alpha or P-AMPK alpha abundance in liver or skeletal muscle. We have, therefore, demonstrated that AMPK alpha responds to signals of increased nutrient availability in the fetal liver. Suppression of hepatic AMPK phosphorylation may contribute to increased glucose production, and basal hyperglycemia, present in lambs of overfed ewes in early postnatal life.