Abstract
Transforming growth factor (TGF)-beta is a potent inhibitor of adipocyte differentiation. To identify which adipocyte transcription factors might be targeted by TGF-beta, we overexpressed key adipogenic transcription factors, C/EBPbeta, C/EBPdelta, or peroxisome proliferator-activated receptor (PPAR) gamma in NIH3T3 cells and tested the ability of TGF-beta to block adipogenesis. We show that TGF-beta inhibits adipocyte differentiation driven by either C/EBPbeta or C/EBPdelta without affecting C/EBP protein expression levels, suggesting that these C/EBPs are a direct target of TGF-beta action. Because TGF-beta inhibits adipogenesis by signaling through Smad3, we examined physical and functional interactions of Smad3 and Smad4 with C/EBPbeta, C/EBPdelta, and PPARgamma2. C/EBPbeta and C/EBPdelta were found to physically interact with Smad3 and Smad4, and Smad3 cooperated with Smad4 and TGF-beta signaling to repress the transcriptional activity of C/EBPs. Thus, repression of the activity of C/EBPs by Smad3/4 at C/EBP binding sites inhibited transcription from the PPARgamma2 and leptin promoters. In contrast, PPARgamma interacted only very weakly with Smad3 and its transcriptional activity was not repressed by Smad3/4 or in response to TGF-beta. Smad3/4 did not reduce the ability of C/EBP to bind to its cognate DNA sequence, but repressed transcription by inhibiting the transactivation function of C/EBP.
Highlights
Cell differentiation requires changes in protein expression patterns to allow manifestation of a specialized phenotype from a precursor state
To address whether Transforming growth factor (TGF)- inhibits the function of individual adipocyte transcription factors, we generated NIH3T3 cell lines stably infected with retroviruses encoding C/EBP, C/EBP␦, C/EBP␣, or peroxisome proliferator-activated receptor (PPAR)␥
TGF-/Smad3 Signaling Inhibits Adipogenic Differentiation Primarily through Functional Repression of C/EBP and C/EBP␦—We previously observed that inhibition of adipogenesis by TGF- was accompanied by reduced mRNA levels for PPAR␥, C/EBP␣, and ADD1/SREBP1c, but not of C/EBP and -␦ [20]
Summary
Cell differentiation requires changes in protein expression patterns to allow manifestation of a specialized phenotype from a precursor state. C/EBP␣ cooperates with PPAR␥2 to activate adipocyte gene expression, and both factors are required for adipocyte differentiation [16]. Any of these transcription factors could represent targets for regulation by signaling pathways that affect adipogenesis. In animal models of obesity [23] and humans with obesity, TGF-1 expression is increased, correlating directly with body mass index and increased expression of PAI-1 (plasminogen activator inhibitor-1), which in turn are closely related to insulin resistance [27] These observations contrast with the ability of TGF- to strongly inhibit adipocyte differentiation.
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