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This version published online on August 19, 2004
Molecular Endocrinology, doi:10.1210/me.2004-0213
A more recent version of this article appeared on November 1, 2004
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Submitted on May 25, 2004
Accepted on July 27, 2004

Hepatic C/EBP{alpha} mediates induction of lipogenesis and regulation of glucose homeostasis in leptin-deficient mice

Kimihiko Matsusue, Oksana Gavrilova, Gilles Lambert, H. Bryan Brewer Jr, Jerrold M. Ward, Yusuke Inoue, Derek LeRoith, and Frank J. Gonzalez*

Laboratory of Metabolism, National Cancer Institute, and Comparative Medicine Branch, National Institutes of Allergy and Infectious Diseases, Molecular Disease Branch, National Heart, Lung, and Blood Instituteand Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, INSERM U 539, Hotel Dieu, 44000 Nantes, France

* To whom correspondence should be addressed. E-mail: fjgonz{at}helix.nih.gov.

CCAAT/enhancer binding protein {alpha} (C/EBP{alpha}) is a critical factor in glucose metabolism in the neonate as revealed by conventional C/EBP{alpha}-null mice that do not survive beyond the first day after birth due to severe hypoglycemia and a deficiency in hepatic glycogen accumulation. To elucidate the function of C/EBP{alpha} in leptin-deficient mouse (ob/ob) liver, a C/EBP{alpha}-liver null mouse on an ob/ob background (ob/ob-C/EBP{alpha}/Cre+) was produced using a floxed C/EBP{alpha} allele and Cre recombinase under control of the albumin promoter (AlbCre). The C/EBP{alpha}-deficient liver in ob/ob mice had significantly decreased triglyceride content compared with equivalent mice lacking the AlbCre transgene (ob/ob-C/EBP{alpha}/Cre-). Expression of genes involved in lipogenesis including fatty acid synthase, acetyl-CoA carboxylase, stearoyl-CoA desaturase 1 and ATP-citrate lyase dramatically decreased in ob/ob-C/EBP{alpha}/Cre+ mouse liver. Induction of these lipogenic genes by a high carbohydrate diet caused an exacerbation in the development of fatty liver and an increase in liver size, hepatic triglyceride and cholesterol contents in ob/ob-C/EBP{alpha}/Cre- mice but not in ob/ob-C/EBP{alpha}/Cre+ mice. Deficiency in hepatic C/EBP{alpha} expression caused an exacerbation of hyperglycemia due to decreased insulin secretion. Taken together, these results indicate that hepatic C/EBP{alpha} plays a critical role in the acceleration of lipogenesis in ob/ob mice and in glucose homeostasis by the indirect regulation of insulin secretion.
Key words: diabetes • C/EBP • leptin • diabetes • ob/ob • hepatosteatosis • conditional knockout




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