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This Article Full Text Full Text (PDF) All Versions of this Article: 294/2/E365    most recent 00639.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rozance, P. J. Articles by Hay, W. W. Search for Related Content PubMed PubMed Citation Articles by Rozance, P. J. Articles by Hay, W. W., Jr.

Chronic late-gestation hypoglycemia upregulates hepatic PEPCK associated with increased PGC1 mRNA and phosphorylated CREB in fetal sheep

¹Perinatal Research Center, Department of Pediatrics, School of Medicine, University of Colorado Denver and Health Sciences Center, Aurora, Colorado; ²Agricultural Research Complex, Department of Animal Sciences, University of Arizona, Tucson, Arizona; and ³Department of Obstetrics and Gynaecology, University of Western Ontario, London, Ontario, Canada

Submitted 2 October 2007 ; accepted in final form 29 November 2007

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- coactivator-1 mRNA and phosphorylation of cAMP response element binding protein at Ser¹³³ were both increased, with no change in Akt, forkhead transcription factor FoxO1, hepatocyte nuclear factor-4, or CCAAT enhancer binding protein-β. These results demonstrate that chronic fetal hypoglycemia triggers signals that can activate gluconeogenesis in the fetal liver.

glucose; gluconeogenesis; cortisol; cAMP response element binding protein; peroxisome proliferator-activated receptor- coactivator-1; phosphoenolpyruvate carboxykinase

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