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Molecular and Cellular Biology, October 2004, p. 8671-8680, Vol. 24, No. 19
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.19.8671-8680.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Phosphorylation of C/EBPß at a Consensus Extracellular Signal-Regulated Kinase/Glycogen Synthase Kinase 3 Site Is Required for the Induction of Adiponectin Gene Expression during the Differentiation of Mouse Fibroblasts into Adipocytes

Bae-Hang Park, Li Qiang, and Stephen R. Farmer*

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

Received 22 January 2004/ Returned for modification 18 March 2004/ Accepted 17 June 2004

Stimulation of adipogenesis in mouse preadipocytes requires C/EBPß as well as activation of the MEK/extracellular signal-regulated kinase (ERK) signaling pathway. In this study, we demonstrate that phosphorylation of C/EBPß at a consensus ERK/glycogen synthase kinase 3 (GSK3) site regulates adiponectin gene expression during the C/EBPß-facilitated differentiation of mouse fibroblasts into adipocytes. First, we show that exposure of 3T3-L1 preadipocytes to insulin, dexamethasone (DEX), and isobutylmethylxanthine (MIX) leads to the phosphorylation of C/EBPß at threonine 188. Pretreating the cells with a MEK1-specific inhibitor (U0126) significantly attenuates this activity. Similarly, these effectors activate the phosphorylation of T188 within an ectopic C/EBPß overexpressed in Swiss mouse fibroblasts, and this event involves both MEK1 and GSK3 activity. We further show that expression of C/EBPß (p34kD LAP isoform) in Swiss mouse fibroblasts exposed to DEX, MIX, and insulin induces expression of peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) and some adiponectin but that it does not activate expression of FABP4/aP2. In fact, complete conversion of these fibroblasts into lipid-laden adipocytes, which includes activation of FABP4 and adiponectin expression, requires their exposure to a potent PPAR{gamma} ligand such as troglitazone. Expression of a mutant C/EBPß in which threonine 188 has been modified to alanine (C/EBPß T188A) can induce PPAR{gamma} production in the mouse fibroblasts, but it is incapable of stimulating adiponectin expression in the absence or presence of troglitazone. Interestingly, replacement of T188 with aspartic acid creates a C/EBPß molecule (C/EBPß T188D) that possesses adipogenic activity similar to that of the wild-type molecule. The absence of adiponectin expression correlates with a reduced amount of C/EBP{alpha} in the adipocytes expressing the T188A mutant suggesting that C/EBP{alpha} is required for expression of adiponectin. In fact, ectopic expression of PPAR{gamma} in C/EBP{alpha}-deficient fibroblasts (NIH 3T3 cells) produces a modest amount of adiponectin, whereas expression of both PPAR{gamma} and C/EBP{alpha} in NIH 3T3 cells facilitates production of abundant quantities of adiponectin. These data demonstrate that phosphorylation of C/EBPß at a consensus ERK/GSK3 site is required for both C/EBP{alpha} and adiponectin gene expression during the differentiation of mouse fibroblasts into adipocytes.

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

Molecular and Cellular Biology, October 2004, p. 8671-8680, Vol. 24, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.19.8671-8680.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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