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


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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    ABSTRACT: Adipogenesis is the process by which precursor stem cells differentiate into lipid laden adipocytes. Adipogenesis is regulated by a complex and highly orchestrated gene expression program. In mammalian cells, the peroxisome proliferator-activated receptor γ (PPARγ), and the CCAAT/enhancer binding proteins (C/EBPs) such as C/EBPα,β and δ are considered the key early regulators of adipogenesis, while fatty acid binding protein 4 (FABP4), adiponectin, and fatty acid synthase (FAS) are responsible for the formation of mature adipocytes. Excess accumulation of lipids in the adipose tissue leads to obesity, which is associated with cardiovascular diseases, type II diabetes and other pathologies. Thus, investigating adipose tissue development and the underlying molecular mechanisms is vital to develop therapeutic agents capable of curbing the increasing incidence of obesity and related pathologies. In this review, we address the process of adipogenic differentiation, key transcription factors and proteins involved, adipogenic regulators and potential anti-adipogenic bioactive molecules.
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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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    ABSTRACT: Background: Lipid metabolism dysfunction leading to excess fat deposits (obesity) may cause tumor (cancer) development. Both obesity and cancer are the epicenter of important medical issues. Lipid metabolism and cell death/proliferation are controlled by biochemical and molecular pathways involving many proteins, and organelles; alteration in these pathways leads to fat accumulation or tumor growth. Mammalian Krüppel-like factors, KLFs play key roles in both lipid metabolism and tumor development. Scope of review: Substantial epidemiological and clinical studies have established strong association of obesity with a number of human cancers. However, we need more experimental verification to determine the exact role of this metabolic alteration in the context of tumor development. A clear understanding of molecules, pathways and the mechanisms involved in lipid metabolism and cell death/proliferation will have important implications in pathogenesis, and prevention of these diseases. Major conclusion: The regulatory role of KLFs, in both cell death/proliferation and lipid metabolism suggests a common regulation of both processes. This provides an excellent model for delivering a precise understanding of the mechanisms linking altered expression of KLFs to obesity and tumor development. General significance: Currently, mouse and rats are the models of choice for investigating disease mechanisms and pharmacological therapies but a genetic model is needed for a thorough examination of KLF function in vivo during the development of an organism. The worm Caenorhabditis elegans is an ideal model to study the connectivity between lipid metabolism and cell death/proliferation.
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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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