Submitted on October 2, 2007
Accepted on November 29, 2007
Chronic Late Gestation Hypoglycemia Up-Regulates Hepatic PEPCK Associated with Increased PGC1
mRNA and pCREB in Fetal Sheep
Paul J. Rozance1*, Sean W. Limesand2, James S. Barry1, Laura D Brown1, Stephanie R. Thorn1, Dan LoTurco3, Timothy Regnault4, Jacob E. Friedman3, and William W. Hay, Jr.3
1 Perinatal Research Center, University of Colorado Health Science Center, Aurora, Colorado, United States
2 Department of Animal Sciences, University of Arizona, Tucson, Arizona, United States
3 Perinatal Research Center, University of Colorado Health Sciences Center, Aurora, Colorado, United States
4 Dept of Obstetrics & Gynecology, University of Western Ontario, London, Canada
* To whom correspondence should be addressed. E-mail: paul.rozance{at}uchsc.edu.
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 weeks of fetal hypoglycemia during late gestation on enzymes responsible for hepatic gluconeogenesis, focusing on the insulin signaling pathway, transcription factors, and coactivators which regulate gluconeogenesis. Hepatic PEPCK 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. PGC1
mRNA and phosphorylation of CREB at serine 133 were both increased, with no change in Akt, FOXO1, HNF4, or C/EBP
. These results demonstrate that chronic fetal hypoglycemia triggers signals which can activate gluconeogenesis in the fetal liver.
