Hypoglycemia and impaired hepatic glucose production in mice with a deletion of the C/EBPbeta gene

J Clin Invest. 1999 Jan;103(2):207-13. doi: 10.1172/JCI4243.


The transcription factor CCAAT/enhancer-binding protein beta (C/EBPbeta) is enriched in liver and adipose tissue and controls the expression of a wide variety of genes coding for important metabolic pathways, including gluconeogenesis and lipid synthesis. To investigate the role of C/EBPbeta on glucose homeostasis, we studied mice with a targeted deletion of the gene for C/EBPbeta-/- mice. Adult C/EBPbeta-/- mice have hypoglycemia after an 18-hour fast, accompanied by lower hepatic glucose production (40% of that of wild-type mice), with no change in plasma insulin and a lower concentration of plasma free fatty acids (FFA). Glucagon infusion during a pancreatic clamp acutely stimulated hepatic glucose production by 38% in wild-type animals, with no change detected in C/EBPbeta-/- mice. Unexpectedly, both the basal and glucagon-stimulated hepatic cyclic adenosine monophosphate (cAMP) levels were lower in C/EBPbeta-/- mice, indicating an essential role for C/EBPbeta in controlling proximal signal transduction. Fasting hypoglycemia was associated with normal levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) gene expression, however net liver glycogenolysis was impaired in C/EBPbeta-/- mice. FFA release from isolated adipose tissue in response to epinephrine was 68% lower in C/EBPbeta-/- mice than in control animals; however, N6,O2'-dibutyryladenosine (Bt2) cAMP stimulated a twofold increase in FFA release in C/EBPbeta-/- compared with no further increase in wild-type mice. Because a deletion in the gene for C/EBPbeta reduces blood glucose and circulating FFA, it could be an important therapeutic target for the treatment of non-insulin-dependent diabetes and possibly obesity, based on designing antagonists that decrease C/EBPbeta activity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Proteins
  • Cyclic AMP / pharmacology
  • DNA-Binding Proteins / genetics*
  • Epinephrine / pharmacology
  • Female
  • Glucagon / pharmacology
  • Glucokinase / genetics
  • Glucose / metabolism*
  • Glucose-6-Phosphatase / genetics
  • Hypoglycemia / genetics*
  • Hypoglycemia / metabolism
  • Lipolysis / genetics
  • Liver / metabolism*
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / genetics*
  • Phosphoenolpyruvate Carboxykinase (GTP) / genetics
  • RNA, Messenger / genetics
  • Somatostatin / pharmacology


  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins
  • Nuclear Proteins
  • RNA, Messenger
  • Somatostatin
  • Glucagon
  • Cyclic AMP
  • Glucokinase
  • Glucose-6-Phosphatase
  • Phosphoenolpyruvate Carboxykinase (GTP)
  • Glucose
  • Epinephrine