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Am J Physiol Endocrinol Metab 294: E365-E370, 2008. First published December 4, 2007; doi:10.1152/ajpendo.00639.2007
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Chronic late-gestation hypoglycemia upregulates hepatic PEPCK associated with increased PGC1{alpha} mRNA and phosphorylated CREB in fetal sheep

Paul J. Rozance,1 Sean W. Limesand,2 James S. Barry,1 Laura D. Brown,1 Stephanie R. Thorn,1 Dan LoTurco,1 Timothy R. H. Regnault,1,3 Jacob E. Friedman,1 and William W. Hay, Jr.1

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-{gamma} coactivator-1{alpha} 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{alpha}, 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-{gamma} coactivator-1{alpha}; phosphoenolpyruvate carboxykinase



Address for reprint requests and other correspondence: P. J. Rozance, Perinatal Research Center, Dept. of Pediatrics, Univ. of Colorado Health Sciences Center, P.O. Box 6508, MS F441, Aurora, CO 80045 (e-mail: Paul.Rozance{at}UCHSC.edu)







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