Maternal overnutrition suppresses the phosphorylation of 5'-AMP-activated protein kinase in liver, but not skeletal muscle, in the fetal and neonatal sheep.
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 approximately 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 AMPKalpha1 and AMPKalpha2 mRNA was determined by quantitative RT-PCR (qRT-PCR). The abundance of AMPKalpha and phospho-AMPKalpha (P-AMPKalpha) was determined by Western blot analysis, and the proportion of the total AMPKalpha pool that was phosphorylated in each sample (%P-AMPKalpha) was determined. The ratio of AMPKalpha2 to AMPKalpha1 mRNA expression was lower in fetuses compared with lambs in both liver and muscle, independent of maternal nutrition. Hepatic %P-AMPKalpha was lower in both fetuses and lambs in the Overfed group and %P-AMPKalpha 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 AMPKalpha or P-AMPKalpha abundance in liver or skeletal muscle. We have, therefore, demonstrated that AMPKalpha 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.
Philp
L K
LK
Early Origins of Adult Health Research Group, Sansom Institute, University of South Australia, Adelaide 5001, Australia.
Muhlhausler
B S
BS
Janovska
A
A
Wittert
G A
GA
Duffield
J A
JA
McMillen
I C
IC
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001786:Blood Glucose / Q000378:metabolism; D015536:Down-Regulation; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D005333:Fetus / Q000201:enzymology; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D005865:Gestational Age; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood; D008099:Liver / Q000196:embryology / Q000201:enzymology*; D039382:Maternal Nutritional Physiological Phenomena; D044343:Overnutrition / Q000196:embryology / Q000201:enzymology*; D010766:Phosphorylation; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D021122:Protein Subunits; D052097:Quadriceps Muscle / Q000196:embryology / Q000201:enzymology*; D012333:RNA, Messenger / Q000378:metabolism; D012756:Sheep
D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D020738:Leptin; D021122:Protein Subunits; D012333:RNA, Messenger; D055372:AMP-Activated Protein Kinases