CCAAT/enhancer-binding protein beta deletion reduces adiposity, hepatic steatosis, and diabetes in Lepr(db/db) mice

J Biol Chem. 2007 May 25;282(21):15717-29. doi: 10.1074/jbc.M701329200. Epub 2007 Mar 26.


CCAAT/enhancer-binding protein beta (C/EBPbeta) plays a key role in initiation of adipogenesis in adipose tissue and gluconeogenesis in liver; however, the role of C/EBPbeta in hepatic lipogenesis remains undefined. Here we show that C/EBPbeta inactivation in Lepr(db/db) mice attenuates obesity, fatty liver, and diabetes. In addition to impaired adipogenesis, livers from C/EBPbeta(-/-) x Lepr(db/db) mice had dramatically decreased triglyceride content and reduced lipogenic enzyme activity. C/EBPbeta deletion in Lepr(db/db) mice down-regulated peroxisome proliferator-activated receptor gamma2 (PPARgamma2) and stearoyl-CoA desaturase-1 and up-regulated PPARalpha independent of SREBP1c. Conversely, C/EBPbeta overexpression in wild-type mice increased PPARgamma2 and stearoyl-CoA desaturase-1 mRNA and hepatic triglyceride content. In FAO cells, overexpression of the liver inhibiting form of C/EBPbeta or C/EBPbeta RNA interference attenuated palmitate-induced triglyceride accumulation and reduced PPARgamma2 and triglyceride levels in the liver in vivo. Leptin and the anti-diabetic drug metformin acutely down-regulated C/EBPbeta expression in hepatocytes, whereas fatty acids up-regulate C/EBPbeta expression. These data provide novel evidence linking C/EBPbeta expression to lipogenesis and energy balance with important implications for the treatment of obesity and fatty liver disease.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adiposity* / drug effects
  • Adiposity* / genetics
  • Animals
  • CCAAT-Enhancer-Binding Protein-beta / deficiency
  • CCAAT-Enhancer-Binding Protein-beta / metabolism*
  • Cell Line
  • Diabetes Mellitus / genetics
  • Diabetes Mellitus / metabolism*
  • Diabetes Mellitus / therapy
  • Energy Metabolism / drug effects
  • Energy Metabolism / genetics
  • Fatty Liver / genetics
  • Fatty Liver / metabolism*
  • Fatty Liver / therapy
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Hypoglycemic Agents / pharmacology
  • Metformin / pharmacology
  • Mice
  • Mice, Knockout
  • Obesity / genetics
  • Obesity / metabolism*
  • Obesity / therapy
  • PPAR alpha / biosynthesis
  • PPAR gamma / biosynthesis
  • Palmitates / pharmacology
  • Stearoyl-CoA Desaturase / biosynthesis
  • Sterol Regulatory Element Binding Protein 1 / biosynthesis
  • Triglycerides / metabolism


  • CCAAT-Enhancer-Binding Protein-beta
  • Hypoglycemic Agents
  • PPAR alpha
  • PPAR gamma
  • Palmitates
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Triglycerides
  • Metformin
  • Scd1 protein, mouse
  • Stearoyl-CoA Desaturase