CCAAT/enhancer-binding protein β deletion reduces adiposity, hepatic steatosis, and diabetes in Leprdb/db mice

Jill M. Schroeder-Gloeckler, Shaikh Mizanoor Rahman, Rachel C. Janssen, Liping Qiao, Jianhua Shao, Michael Roper, Stephanie J. Fischer, Erin Lowe, David J. Orlicky, James L. McManaman, Carol Palmer, William L. Gitomer, Wan Huang, Robert M. O'Doherty, Thomas C. Becker, Dwight J. Klemm, Dalan R. Jensen, Leslie K. Pulawa, Robert H. Eckel, Jacob E. Friedman

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Abstract

CCAAT/enhancer-binding protein β (C/EBPβ) plays a key role in initiation of adipogenesis in adipose tissue and gluconeogenesis in liver; however, the role of C/EBPβ in hepatic lipogenesis remains undefined. Here we show that C/EBPβ inactivation in Leprdb/db mice attenuates obesity, fatty liver, and diabetes. In addition to impaired adipogenesis, livers from C/EBPβ-/- x Leprdb/db mice had dramatically decreased triglyceride content and reduced lipogenic enzyme activity. C/EBPβ deletion in Leprdb/db mice down-regulated peroxisome proliferator-activated receptor γ2 (PPARγ2) and stearoyl-CoA desaturase-1 and up-regulated PPARα independent of SREBP1c. Conversely, C/EBPβ overexpression in wild-type mice increased PPARγ2 and stearoyl-CoA desaturase-1 mRNA and hepatic triglyceride content. In FAO cells, overexpression of the liver inhibiting form of C/EBPβ or C/EBPβ RNA interference attenuated palmitate-induced triglyceride accumulation and reduced PPARγ2 and triglyceride levels in the liver in vivo. Leptin and the anti-diabetic drug metformin acutely down-regulated C/EBPβ expression in hepatocytes, whereas fatty acids up-regulate C/EBPβ expression. These data provide novel evidence linking C/EBPβ expression to lipogenesis and energy balance with important implications for the treatment of obesity and fatty liver disease.

Original languageEnglish
Pages (from-to)15717-15729
Number of pages13
JournalJournal of Biological Chemistry
Volume282
Issue number21
DOIs
StatePublished - May 25 2007

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    Schroeder-Gloeckler, J. M., Rahman, S. M., Janssen, R. C., Qiao, L., Shao, J., Roper, M., Fischer, S. J., Lowe, E., Orlicky, D. J., McManaman, J. L., Palmer, C., Gitomer, W. L., Huang, W., O'Doherty, R. M., Becker, T. C., Klemm, D. J., Jensen, D. R., Pulawa, L. K., Eckel, R. H., & Friedman, J. E. (2007). CCAAT/enhancer-binding protein β deletion reduces adiposity, hepatic steatosis, and diabetes in Leprdb/db mice. Journal of Biological Chemistry, 282(21), 15717-15729. https://doi.org/10.1074/jbc.M701329200