title: The Krüppel-like factor KLF2 inhibits peroxisome proliferator-activated receptor-gamma expression and adipogenesis.
abstract: Obesity is an important public health problem associated with a number of disease states such as diabetes and arteriosclerosis. As such, an understanding of the mechanisms governing adipose tissue differentiation and function is of considerable importance. We recently reported that the Krüppel-like zinc finger transcription factor KLF15 can induce adipocyte maturation and GLUT4 expression. In this study, we identify that a second family member, KLF2/Lung Krüppel-like factor (LKLF), as a negative regulator of adipocyte differentiation. KLF2 is highly expressed in adipose tissue, and studies in cell lines and primary cells demonstrate that KLF2 is expressed in preadipocytes but not mature adipocytes. Constitutive overexpression of KLF2 but not KLF15 potently inhibits peroxisome proliferator-activated receptor-gamma (PPARgamma) expression with no effect on the upstream regulators C/EBPbeta and C/EBPdelta. However, the expression of C/EBPalpha and SREBP1c/ADD1 (adipocyte determination and differentiation factor-1/sterol regulatory element-binding protein-1), two factors that feedback in a positive manner to enhance PPARgamma function, was also markedly reduced. In addition, transient transfection studies show that KLF2 directly inhibits PPARgamma2 promoter activity (70% inhibition; p < 0.001). Using a combination of promoter mutational analysis and gel mobility shift assays, we have identified a binding site within the PPARgamma2 promoter, which mediates this inhibitory effect. These data identify a novel role for KLF2 as a negative regulator of adipogenesis.
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Sucharita Sen
authors.initials: SS
authors.lastname: Banerjee
authors.forename: Mark W
authors.initials: MW
authors.lastname: Feinberg
authors.forename: Masafumi
authors.initials: M
authors.lastname: Watanabe
authors.forename: Susan
authors.initials: S
authors.lastname: Gray
authors.forename: Richard L
authors.initials: RL
authors.lastname: Haspel
authors.forename: Diane J
authors.initials: DJ
authors.lastname: Denkinger
authors.forename: Rodney
authors.initials: R
authors.lastname: Kawahara
authors.forename: Hans
authors.initials: H
authors.lastname: Hauner
authors.forename: Mukesh K
authors.initials: MK
authors.lastname: Jain
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D051743:CCAAT-Enhancer-Binding Protein-delta; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008957:Models, Genetic; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis*; D012190:Retroviridae / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1; D014018:Tissue Distribution; D015534:Trans-Activators / Q000378:metabolism* / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis*; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D022782:CCAAT-Enhancer-Binding Protein-beta; D022762:CCAAT-Enhancer-Binding Proteins; C497252:CEBPD protein, human; C497253:Cebpd protein, mouse; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C096161:KLF2 protein, human; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; C497387:SREBF1 protein, human; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D015534:Trans-Activators; D014157:Transcription Factors; D051743:CCAAT-Enhancer-Binding Protein-delta; D008156:Luciferases