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J. Biol. Chem., Vol. 281, Issue 52, 40341-40353, December 29, 2006

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Depletion of cAMP-response Element-binding Protein/ATF1 Inhibits Adipogenic Conversion of 3T3-L1 Cells Ectopically Expressing CCAAT/Enhancer-binding Protein (C/EBP) , C/EBP , or PPAR2^*

Keith E. Fox, Dana M. Fankell, Paul F. Erickson, Susan M. Majka, Joseph T. Crossno, Jr., and Dwight J. Klemm^¶1

From the ^¶Research Service, Veterans Affairs Medical Center, and Cardiovascular Pulmonary Research Laboratory, and Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado 80220

The differentiation of preadipocytes to adipocytes is orchestrated by the expression of the "master adipogenic regulators," CCAAT/enhancer-binding protein (C/EBP) , peroxisome proliferator-activated receptor (PPAR), and C/EBP . In addition, activation of the cAMP-response element-binding protein (CREB) is necessary and sufficient to promote adipogenic conversion and prevent apoptosis of mature adipocytes. In this report we used small interfering RNAto deplete CREB and the closely related factor ATF1 to explore the ability of the master adipogenic regulators to promote adipogenesis in the absence of CREB and probe the function of CREB in late stages of adipogenesis. Loss of CREB/ATF1 blocked adipogenic conversion of 3T3-L1 cells in culture or 3T3-F442A cells implanted into athymic mice. Loss of CREB/ATF1 prevented the expression of PPAR, C/EBP , and adiponectin and inhibited the loss of Pref-1. Loss of CREB/ATF1 inhibited adipogenic conversion even in cells ectopically expressing C/EBP , C/EBP , or PPAR2 individually. CREB/ATF1 depletion did not attenuate lipid accumulation in cells expressing both PPAR2 and C/EBP , but adiponectin expression was severely diminished. Conversely ectopic expression of constitutively active CREB overcame the blockade of adipogenesis due to depletion of C/EBP but not due to loss of PPAR2 or C/EBP . Depletion of CREB/ATF1 did not suppress the expression of C/EBP as we had previously observed using dominant negative forms of CREB. Finally results are presented showing that CREB promotes PPAR2 gene transcription. The results indicate that CREB and ATF1 play a central role in adipogenesis because expression of individual master adipogenic regulators is unable to compensate for their loss. The data also indicate that CREB not only functions during the initiation of adipogenic conversion but also at later stages.

Received for publication, May 26, 2006 , and in revised form, October 26, 2006.

^* This work was supported by National Institutes of Health Grant DK053969 (to D. J. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ To whom correspondence should be addressed: Cardiovascular Pulmonary Research, University of Colorado Health Sciences Center, 4200 East Ninth Ave., Campus Box B-133, Denver, CO 80262. Tel.: 303-315-8107; Fax: 303-315-4871; E-mail: Dwight.Klemm{at}UCHSC.edu.

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