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Molecular and Cellular Biology, January 2008, p. 188-200, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.00992-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Identification of a Domain within Peroxisome Proliferator-Activated Receptor {gamma} Regulating Expression of a Group of Genes Containing Fibroblast Growth Factor 21 That Are Selectively Repressed by SIRT1 in Adipocytes{triangledown} ,{dagger}

Hong Wang, Li Qiang, and Stephen R. Farmer*

Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118

Received 5 June 2007/ Returned for modification 12 July 2007/ Accepted 8 October 2007

Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) activity is regulated through association with ligands that include the thiazolidinedione class of antidiabetic drugs, as well as derivatives of polyunsaturated fatty acids. Induction of PPAR{gamma} target gene expression involves ligand-dependent reconfiguration of the ligand-binding domain (LBD), followed by recruitment of specific transcriptional coactivators. In this study, we have identified an amino acid (F372) within helix 7 of the LBD that is required for the response of PPAR{gamma} to endogenous ligands. Additionally, the data show that this amino acid is also required for expression of a novel subset of adipocyte genes (group 2), including fibroblast growth factor 21 (FGF21), and that the FGF21 gene is a direct target of PPAR{gamma}. Expression of the group 2 genes is selectively repressed by the NAD-dependent deacetylase SIRT1 in mature 3T3-L1 adipocytes, since knockdown of SIRT1 through the constitutive expression of a corresponding RNA interference enhances their expression without affecting the expression of classic adipogenic genes, such as adiponectin and FABP4/aP2. It appears that many of the group 2 genes repressed by SIRT1 in mature adipocytes correspond to the same set of genes that are selectively activated by treatment of fat cells with the PPAR{gamma} ligand, troglitazone. These data support a role for helix 7 of the LBD of PPAR{gamma} in regulating adipocyte function and suggest that inhibition of SIRT1 in adipocytes induces the same insulin-sensitizing action as PPAR{gamma} ligands.

* 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

{triangledown} Published ahead of print on 22 October 2007.

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

Molecular and Cellular Biology, January 2008, p. 188-200, Vol. 28, No. 1
0270-7306/08/$08.00+0     doi:10.1128/MCB.00992-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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