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Molecular and Cellular Biology, September 2009, p. 4714-4728, Vol. 29, No. 17
0270-7306/09/$08.00+0     doi:10.1128/MCB.01899-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

C/EBP and the Corepressors CtBP1 and CtBP2 Regulate Repression of Select Visceral White Adipose Genes during Induction of the Brown Phenotype in White Adipocytes by Peroxisome Proliferator-Activated Receptor Agonists ^,

Cecile Vernochet,¹ Sidney B. Peres,¹ Kathryn E. Davis,² Meghan E. McDonald,¹ Li Qiang,¹ Hong Wang,¹ Philipp E. Scherer,² and Stephen R. Farmer^1*

Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118,¹ Touchstone Diabetes Center, Departments of Internal Medicine and Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas²

Received 16 December 2008/ Returned for modification 23 February 2009/ Accepted 18 June 2009

White adipose tissue (WAT) stores energy in the form of triglycerides, whereas brown tissue (BAT) expends energy, primarily by oxidizing lipids. WAT also secretes many cytokines and acute-phase proteins that contribute to insulin resistance in obese subjects. In this study, we have investigated the mechanisms by which activation of peroxisome proliferator-activated receptor (PPAR) with synthetic agonists induces a brown phenotype in white adipocytes in vivo and in vitro. We demonstrate that this phenotypic conversion is characterized by repression of a set of white fat genes ("visceral white"), including the resistin, angiotensinogen, and chemerin genes, in addition to induction of brown-specific genes, such as Ucp-1. Importantly, the level of expression of the "visceral white" genes is high in mesenteric and gonadal WAT depots but low in the subcutaneous WAT depot and in BAT. Mutation of critical amino acids within helix 7 of the ligand-binding domain of PPAR prevents inhibition of visceral white gene expression by the synthetic agonists and therefore shows a direct role for PPAR in the repression process. Inhibition of the white adipocyte genes also depends on the expression of C/EBP and the corepressors, carboxy-terminal binding proteins 1 and 2 (CtBP1/2). The data further show that repression of resistin and angiotensinogen expression involves recruitment of CtBP1/2, directed by C/EBP, to the minimal promoter of the corresponding genes in response to the PPAR ligand. Developing strategies to enhance the brown phenotype in white adipocytes while reducing secretion of stress-related cytokines from visceral WAT is a means to combat obesity-associated disorders.

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* Corresponding author. Mailing address: Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, Boston, MA 02118. Phone: (617) 638-4186. Fax: (617) 638-5339. E-mail: farmer{at}biochem.bumc.bu.edu

Published ahead of print on 29 June 2009.

Supplemental material for this article may be found at http://mcb.asm.org/.

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Molecular and Cellular Biology, September 2009, p. 4714-4728, Vol. 29, No. 17
0270-7306/09/$08.00+0     doi:10.1128/MCB.01899-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.