Chronic late-gestation hypoglycemia upregulates hepatic PEPCK associated with increased PGC1α mRNA and phosphorylated CREB in fetal sheep

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

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

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-γ coactivator-1α 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-4α, or CCAAT enhancer binding protein-β. These results demonstrate that chronic fetal hypoglycemia triggers signals that can activate gluconeogenesis in the fetal liver.

Original languageEnglish (US)
Pages (from-to)E365-E370
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume294
Issue number2
DOIs
StatePublished - Feb 1 2008

Keywords

  • Coactivator-1α
  • Cortisol
  • Gluconeogenesis
  • Glucose
  • Peroxisome proliferator-activated receptor-γ
  • Phosphoenolpyruvate carboxykinase
  • cAMP response element binding protein

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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