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Molecular and Cellular Biology, October 2007, p. 6818-6831, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.00375-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

TRB3 Blocks Adipocyte Differentiation through the Inhibition of C/EBPß Transcriptional Activity{triangledown}

Olivier Bezy,1 Cecile Vernochet,2 Stephane Gesta,1 Stephen R. Farmer,2 and C. Ronald Kahn1*

Section on Obesity and Hormone Action, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215,1 Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, Boston, Massachusetts 021182

Received 1 March 2007/ Returned for modification 11 April 2007/ Accepted 12 July 2007

TRB3 has been implicated in the regulation of several biological processes in mammalian cells through its ability to influence Akt and other signaling pathways. In this study, we investigated the role of TRB3 in regulating adipogenesis and the activity of adipogenic transcription factors. We find that TRB3 is expressed in 3T3-L1 preadipocytes, and this expression is transiently suppressed during the initial days of differentiation concomitant with induction of C/EBPß. This event appears to be a prerequisite for adipogenesis. Overexpression of TRB3 blocks differentiation of 3T3-L1 cells at a step downstream of C/EBPß. Ectopic expression of TRB3 in mouse fibroblasts also inhibits the C/EBPß-dependent induction of PPAR{gamma}2 and blocks their differentiation into adipocytes. This inhibition of preadipocyte differentiation by TRB3 appears to be the result of two complementary effects. First, TRB3 inhibits extracellular signal-regulated kinase activity, which prevents the phosphorylation of regulatory sites on C/EBPß. Second, TRB3 directly interacts with the DR1 domain of C/EBPß in the nucleus, further inhibiting both its ability to bind its response element and its ability to transactivate the C/EBP{alpha} and a-FABP promoters. Thus, TRB3 is an important negative regulator of adipogenesis that acts at an early step in the differentiation cascade to block the C/EBPß proadipogenic function.

* Corresponding author. Mailing address: Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. Phone: (617)732-2635. Fax: (617)732-2487. E-mail: c.ronald.kahn{at}joslin.harvard.edu

{triangledown} Published ahead of print on 23 July 2007.

Molecular and Cellular Biology, October 2007, p. 6818-6831, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.00375-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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