Chronic late-gestation hypoglycemia upregulates hepatic PEPCK associated with increased PGC1alpha mRNA and phosphorylated CREB in fetal sheep.
Hepatic glucose production is normally activated at birth but has been observed in response to experimental hypoglycemia in fetal sheep. The cellular basis for this process remains unknown. We determined the impact of 2 wk of fetal hypoglycemia during late gestation on enzymes responsible for hepatic gluconeogenesis, focusing on the insulin-signaling pathway, transcription factors, and coactivators that regulate gluconeogenesis. Hepatic phosphoenolpyruvate carboxykinase and glucose-6-phosphatase mRNA increased 12-fold and 7-fold, respectively, following chronic hypoglycemia with no change in hepatic glycogen. Chronic hypoglycemia decreased fetal plasma insulin with no change in glucagon but increased plasma cortisol 3.5-fold. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha mRNA and phosphorylation of cAMP response element binding protein at Ser(133) were both increased, with no change in Akt, forkhead transcription factor FoxO1, hepatocyte nuclear factor-4alpha, or CCAAT enhancer binding protein-beta. These results demonstrate that chronic fetal hypoglycemia triggers signals that can activate gluconeogenesis in the fetal liver.
Rozance
Paul J
PJ
Perinatal Research Center, Department of Pediatrics, University of Colorado Health Sciences Center, Aurora, CO 80045, USA. Paul.Rozance@UCHSC.edu
Limesand
Sean W
SW
Barry
James S
JS
Brown
Laura D
LD
Thorn
Stephanie R
SR
LoTurco
Dan
D
Regnault
Timothy R H
TR
Friedman
Jacob E
JE
Hay
William W
WW
D000818:Animals; D015153:Blotting, Western; D003001:Cloning, Molecular; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism; D005333:Fetus / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D007003:Hypoglycemia / Q000139:chemically induced / Q000201:enzymology; D007328:Insulin; D008099:Liver / Q000201:enzymology*; D008112:Liver Glycogen / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000096:biosynthesis / Q000235:genetics; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000096:biosynthesis*; D010766:Phosphorylation; D011247:Pregnancy; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011972:Receptor, Insulin / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012756:Sheep; D014157:Transcription Factors / Q000096:biosynthesis*; D015854:Up-Regulation / Q000502:physiology
D017362:Cyclic AMP Response Element-Binding Protein; D007328:Insulin; D008112:Liver Glycogen; D012333:RNA, Messenger; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D011972:Receptor, Insulin; D051058:Oncogene Protein v-akt; D005952:Glucose-6-Phosphatase; D019764:Phosphoenolpyruvate Carboxykinase (ATP)