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J. Biol. Chem., Vol. 283, Issue 26, 18002-18011, June 27, 2008

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Phosphorylation of CCAAT/Enhancer-binding Protein Regulates GLUT4 Expression and Glucose Transport in Adipocytes^*

Hyuk C. Cha, Nikhil R. Oak, Sona Kang, Tuan-Ahn Tran, Susumu Kobayashi, Shian-Huey Chiang, Daniel G. Tenen, and Ormond A. MacDougald¹

From the Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109-0622 and Hematology/Oncology Division, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215

The transcription factor CCAAT/enhancer-binding protein (C/EBP) is required during adipogenesis for development of insulin-stimulated glucose uptake. Modes for regulating this function of C/EBP have yet to be determined. Phosphorylation of C/EBP on Ser-21 has been implicated in the regulation of granulopoiesis and hepatic gene expression. To explore the role of Ser-21 phosphorylation on C/EBP function during adipogenesis, we developed constructs in which Ser-21 was mutated to alanine (S21A) to model dephosphorylation. In two cell culture models deficient in endogenous C/EBP, enforced expression of S21A-C/EBP resulted in normal lipid accumulation and expression of many adipogenic markers. However, S21A-C/EBP had impaired ability to activate the Glut4 promoter specifically, and S21A-C/EBP expression resulted in diminished GLUT4 and adiponectin expression, as well as reduced insulin-stimulated glucose uptake. No defects in insulin signaling or GLUT4 vesicle trafficking were identified with S21A-C/EBP expression, and when exogenous GLUT4 expression was enforced to normalize expression in S21A-C/EBP cells, insulin-responsive glucose transport was reconstituted, suggesting that the primary defect was a deficit in GLUT4 levels. Mice in which endogenous C/EBP was replaced with S21A-C/EBP displayed reduced GLUT4 and adiponectin protein expression in epididymal adipose tissue and increased blood glucose compared with wild-type littermates. These results suggest that phosphorylation of C/EBP on Ser-21 may regulate adipocyte gene expression and whole body glucose homeostasis.

Received for publication, January 16, 2008 , and in revised form, April 1, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant DK62876 (to O. A. M.). This work was also supported by American Diabetes Association Grant 1-06-RA-88, by Fellowship 5-T32-HD007505 from the Center for Organogenesis (to H. C. C.), and by fellowships from the Horace Rackham School of Graduate Studies (to S. K.). 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: 1301 E. Catherine St., Ann Arbor, MI 48109-0622. Tel.: 734-647-4880; Fax: 734-936-8813; E-mail: macdouga{at}umich.edu.

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