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J. Biol. Chem., Vol. 282, Issue 21, 15717-15729, May 25, 2007

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CCAAT/Enhancer-binding Protein Deletion Reduces Adiposity, Hepatic Steatosis, and Diabetes in Lepr^db/db Mice^*

From the ^aDepartment of Pediatrics, ^bDepartment of Pathology, ^cDepartment of Obstetrics and Gynecology, ^dDepartment of Physiology and Biophysics, ⁱDepartment of Biochemistry and Molecular Genetics, ^jDepartment of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Colorado at Denver and Health Sciences Center, Aurora, Colorado 80045, ^eRenal and ^hPulmonary Sections, Research Service, Veterans Affairs Medical Center, Denver, Colorado 80220, ^fDepartment of Medicine, Division of Endocrinology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, and ^gDivision of Endocrinology, Nutrition, and Metabolism, Duke University Medical Center, Durham, North Carolina 27704

CCAAT/enhancer-binding protein (C/EBP) plays a key role in initiation of adipogenesis in adipose tissue and gluconeogenesis in liver; however, the role of C/EBP in hepatic lipogenesis remains undefined. Here we show that C/EBP inactivation in Lepr^db/db mice attenuates obesity, fatty liver, and diabetes. In addition to impaired adipogenesis, livers from C/EBP^-/- x Lepr^db/db mice had dramatically decreased triglyceride content and reduced lipogenic enzyme activity. C/EBP deletion in Lepr^db/db mice down-regulated peroxisome proliferator-activated receptor 2 (PPAR2) and stearoyl-CoA desaturase-1 and up-regulated PPAR independent of SREBP1c. Conversely, C/EBP overexpression in wild-type mice increased PPAR2 and stearoyl-CoA desaturase-1 mRNA and hepatic triglyceride content. In FAO cells, overexpression of the liver inhibiting form of C/EBP or C/EBP RNA interference attenuated palmitate-induced triglyceride accumulation and reduced PPAR2 and triglyceride levels in the liver in vivo. Leptin and the anti-diabetic drug metformin acutely down-regulated C/EBP expression in hepatocytes, whereas fatty acids up-regulate C/EBP expression. These data provide novel evidence linking C/EBP expression to lipogenesis and energy balance with important implications for the treatment of obesity and fatty liver disease.

Received for publication, February 15, 2007 , and in revised form, March 19, 2007.

^* This work was supported by National Institutes of Health Grants DK59767 and P30-DK-48520 (to J. E. F.), DK-058855 and DK-072162 (to R. M. O.), HD-045962 and HD-38129 (to J. L. M.), U01-DK-56047 (to T. C. B.), DK-53969 (to D. J. K.), and DK-26356 (to R. H. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² Present address: Physiology, Pharmacology, Metabolism and Cardiovascular Science, Medical University of Ohio at Toledo, Toledo, OH 43614.

³ Present address: Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KY 40536.

⁴ To whom correspondence should be addressed: Depts. of Pediatrics and Biochemistry and Molecular Genetics, UCDHSC-Mail Stop F-8106, P. O. Box 6511, Aurora, CO 80045. Tel.: 303-724-3983; Fax: 303-724-3920; E-mail: jed.friedman{at}uchsc.edu.

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