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J. Biol. Chem., Vol. 280, Issue 46, 38689-38699, November 18, 2005

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Metabolic Response of Mice to a Postnatal Ablation of CCAAT/Enhancer-binding Protein ^*

Jianqi Yang1, Colleen M. Croniger, Julie Lekstrom-Himes, Pu Zhang, Maris Fenyus, Daniel G. Tenen, Gretchen J. Darlington¶, and Richard W. Hanson

From the Departments of Biochemistry and Nutrition, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4935, the Harvard Institutes of Medicine, Harvard University School of Medicine, Boston, Massachusetts 02115, and the ^¶Huffington Center for Aging, Baylor College of Medicine, Houston, Texas 77030

Although CCAAT/enhancer-binding protein (C/EBP) is essential for initiating or sustaining several metabolic processes during the perinatal period, the consequences of total ablation of C/EBP during postnatal development have not been investigated. We have created a conditional knock-out model in which the administration of poly(I:C) caused a virtually total deletion of c/ebp (C/EBP^/- mice) in the liver, spleen, white and brown adipose tissues, pancreas, lung, and kidney of the mice. C/EBP itself was completely ablated in the liver by day 4 after the injection of poly(I:C). There was no noticeable change in phenotype during the first 15 days after the injection. The mice maintained a normal level of fasting blood glucose and responded to the diabetogenic action of streptozotocin. From day 16 onward, the mice developed hypophagia, exhibited severe weight loss, lost triglyceride in white but not brown adipose tissue, became hypoglycemic and hypoinsulinemic, depleted their hepatic glycogen, and developed fatty liver. They also exhibited lowered plasma levels of free fatty acid, triglyceride, and cholesterol, as well as marked changes in hepatic mRNA for C/EBP, peroxisome proliferator-activated receptor , sterol regulatory element-binding protein 1, hydroxymethylglutaryl-coenzyme A reductase, and apolipoproteins. Although basal levels of hepatic mRNA for the cytosolic isoform of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase were reduced, transcription of the genes for these enzymes was inducible by dibutyryl cyclic AMP in C/EBP^/- mice. The animals died about 1 month after the injection of poly(I:C). These findings demonstrate that C/EBP is essential for the survival of animals during postnatal life and that its ablation leads to distinct biphasic change in metabolic processes.

Received for publication, March 30, 2005 , and in revised form, August 19, 2005.

^* This work was supported by National Institutes of Health Grants DK 25541 and DK 58620 (to R. W. H.), DK 53045 (to G. J. D.), and HL 56745 (to D. G. T.). 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 To whom correspondence should be addressed: Dept. of Biochemistry, Case Western Reserve University School of Medicine, Cleveland OH 44106-4935. Tel.: 216-368-3634; Fax: 216-368-4544; E-mail: jxy22{at}pop.cwru.edu.

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