GCN2 regulates the CCAAT enhancer binding protein beta and hepatic gluconeogenesis

Am J Physiol Endocrinol Metab. 2013 Oct 15;305(8):E1007-17. doi: 10.1152/ajpendo.00063.2013. Epub 2013 Jul 30.


Mice deficient for general control nondepressible-2 (Gcn2) either globally or specifically in the liver display reduced capacity to maintain glucose homeostasis during fasting, suggesting the hypothesis that GCN2 may regulate gluconeogenesis (GNG), which normally plays a key role maintaining peripheral glucose homeostasis. Gcn2-deficient mice exhibit normal insulin sensitivity and plasma insulin but show reduced GNG when administered pyruvate, a gluconeogenic substrate. The basal expression of phosphoenolpyruvate carboxykinase, a rate-limiting enzyme in GNG, is abnormally elevated in Gcn2 knockout (KO) mice in the fed state but fails to be further induced during fasting. The level of tricarboxylic acid cycle intermediates, including malate and oxaloacetate, and the NADH-to-NAD(+) ratio are perturbed in the liver of Gcn2 KO mice either in the fed or fasted state, which may directly impinge upon GNG. Additionally, the expression of the CCAAT enhancer-binding protein-β (C/EBPβ) in the liver fails to be induced in Gcn2 KO mice after 24 h fasting, and the liver-specific Cebpβ KO mice show reduced fasting GNG similar to that seen in Gcn2-deficient mice. Our study demonstrates that GCN2 is important in maintaining GNG in the liver, which is likely to be mediated through regulation of C/EBPβ.

Keywords: general control nondepressible-2; gluconeogenesis; glucose homeostasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • CCAAT-Enhancer-Binding Protein-beta / biosynthesis
  • CCAAT-Enhancer-Binding Protein-beta / genetics
  • CCAAT-Enhancer-Binding Protein-beta / metabolism*
  • Cells, Cultured
  • Citric Acid Cycle
  • Gluconeogenesis*
  • Insulin Resistance
  • Liver / cytology
  • Liver / enzymology
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological*
  • Phosphoenolpyruvate Carboxykinase (GTP) / biosynthesis
  • Phosphoenolpyruvate Carboxykinase (GTP) / genetics
  • Phosphoenolpyruvate Carboxykinase (GTP) / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • RNA, Messenger / metabolism
  • Up-Regulation*


  • CCAAT-Enhancer-Binding Protein-beta
  • Cebpb protein, mouse
  • RNA, Messenger
  • Eif2ak4 protein, mouse
  • Protein Serine-Threonine Kinases
  • Phosphoenolpyruvate Carboxykinase (GTP)