The Krüppel-like Factor KLF2 Inhibits Peroxisome Proliferator-activated Receptor-γ Expression and Adipogenesis

Masafumi Watanabe,Sucharita Sen Banerjee,Richard L. Haspel,Mark W. Feinberg,Hans Hauner,Susan Gray,Diane J. Denkinger,Mukesh K. Jain,Rodney Kawahara

doi:10.1074/jbc.m210859200

Masafumi Watanabe, Sucharita Sen Banerjee + Show 7 more

Open Access

https://doi.org/10.1074/jbc.m210859200

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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.

Highlights

Obesity is recognized as a worldwide public health problem that contributes to a wide range of disease conditions [1, 2]
We identify that a second family member, KLF2/Lung Kruppel-like factor (LKLF), as a negative regulator of adipocyte differentiation
In this report we provide evidence that KLF2 can function as a negative regulator of adipogenesis via inhibition of peroxisome proliferator-activated receptor (PPAR)␥

Summary

Introduction

Obesity is recognized as a worldwide public health problem that contributes to a wide range of disease conditions [1, 2]. Studies to date suggest that C/EBP␤ and C/EBP␦ induce PPAR␥, which in turn initiates the adipogenic program [3, 4] Both gain and loss of function experiments argue strongly that PPAR␥ is necessary and sufficient to promote fat cell differentiation [5, 6]. Recent studies using C/EBP␣ null fibroblasts suggest that the critical role of this factor is to induce and maintain PPAR␥ levels as well as to confer insulin sensitivity to adipocytes [7]. Kruppel-like factors are zinc finger proteins that constitute an important class of transcriptional regulators. Previous studies show that Kruppel-like proteins typically regulate critical aspects of cellular differentiation and function in diverse cell types [13,14,15,16]. In this report we provide evidence that KLF2 can function as a negative regulator of adipogenesis via inhibition of PPAR␥

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