Article

Transcriptional Regulation of Adipogenesis by KLF4

Laboratory of Molecular Genetics, Rockefeller University, New York, NY 10021, USA.
Cell Metabolism (Impact Factor: 17.57). 05/2008; 7(4):339-47. DOI: 10.1016/j.cmet.2008.02.001
Source: PubMed

ABSTRACT

While adipogenesis is known to be controlled by a complex network of transcription factors, less is known about the transcriptional cascade that initiates this process. We report here the characterization of Krüppel-like factor 4 (KLF4) as an essential early regulator of adipogenesis. Klf4 is expressed in 3T3-L1 cells within 30 min after exposure to a standard adipogenic cocktail of insulin, glucocorticoids, and IBMX. Knockdown of KLF4 inhibits adipogenesis and downregulates C/EBPbeta levels. KLF4 binds directly to the C/EBPbeta (Cebpb) promoter as shown by chromatin immunoprecipitation and gel shift assays and, together with Krox20, cooperatively transactivates a C/EBPbeta reporter. C/EBPbeta knockdown increases levels of KLF4 and Krox20, suggesting that C/EBPbeta normally suppresses Krox20 and KLF4 expression via a tightly controlled negative feedback loop. KLF4 is specifically induced in response to cAMP, which by itself can partially activate adipogenesis. These data suggest that KLF4 functions as an immediate early regulator of adipogenesis to induce C/EBPbeta.

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Available from: Zhu Chen, Mar 08, 2014
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    • "In 3T3-L1 cells, KLF4 is expressed within the first 30 min and peaks at around 2 h after exposure to an adipogenic cocktail consisting of insulin, glucocorticoids and IBMX[63]. Further analysis shows that knockdown of KLF4 inhibits adipogenesis and down regulates the expression of C/EBPβ[63].Ó PPARγ, C/EBPα, and SREBP1 expression GATA binding protein 2 and GATA binding protein 3 Mouse preadipocytes Inhibited adipogenesis[74]Ó PPARγ expression 3T3-F442A preadipocytes Formation of protein complexes with C/EBPα and C/EBPβ[75]Preadipocyte factor-1 3T3-L1 preadipocytes "
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    • "The designated cells undergo a terminal differentiation that is apparent by both the production of lipid droplets and the emergence of many metabolic factors unique to a developed fat cell. During the entire differentiation process there are several essential molecular interactions that occur among members of C/EBP, the PPAR and ADD1/SREBP1c [132]. C/EBPβ and C/ EBPδ induce PPARγ, which in turn initiates the adipogenic program that is required to promote fat cell differentiation [8] [133]. "
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    • "Most of these are highly enriched (>10-fold) in the C/EBPb immunoprecipitation compared with the nonspecific immunoglobulin G (IgG) control, indicating a strong and specific association with C/EBPb. Several of the transcription factors identified as C/EBPb-interacting proteins by proteomics analysis have also been shown to regulate the early phase of adipocyte differentiation , e.g., KLF4 (Birsoy et al., 2008), KLF5 (Oishi et al., 2011), GR (Siersbaek et al., 2011; Steger et al., 2010), and PBX1 (Monteiro et al., 2011), clearly indicating that our approach is a powerful strategy for identifying biologically meaningful regulators of the differentiation process. A comparison of the identified proteins with our previously published de novo motif analysis of DNA sequences at DHS regions identified at the 4 hr time point (Siersbaek et al., 2011; Figure S1A, right) revealed binding motifs for many of the transcription factors identified as C/EBPb-associated proteins (Figure 2C). "
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