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Transcription factor Snail is a novel regulator of adipocyte differentiation via inhibiting the expression of peroxisome proliferator-activated receptor γ

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Abstract

Snail belongs to the superfamily of zinc-finger transcription factors and plays a crucial role in processes regulating cell fate, such as the formation of mesoderm and initiation of epithelial–mesenchymal transition. We have previously discovered that Snail modulates adiponectin expression in 3T3-L1 cells during adipogenesis. In the present study, we elucidated the functional role of Snail in adipocyte differentiation and its underlying molecular mechanism. Snail expression was dramatically decreased during adipogenesis in 3T3-L1 cells. Overexpression of Snail blocked adipocyte differentiation by suppressing the expression of peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT-enhancer-binding protein alpha, while knockdown of Snail expression stimulated adipogenesis in 3T3-L1 cells. Chromatin immunoprecipitation assay and luciferase assay showed that Snail inhibits the transcriptional activity of the PPARγ gene by directly binding to the E-box motifs in the PPARγ promoter. Wnt10b induced phosphorylation of glycogen synthase kinase 3 beta (GSK3β), leading to inhibition of adipogenesis in 3T3-L1 cells in accordance with increased expression of Snail, whereas adipogenic capacity was restored in Snail siRNA-transfected preadipocytes. LiCl (a GSK3β inhibitor)-treated cells also showed increased expression of Snail, with a reduced adipogenic potential. Snail-overexpressing 3T3-F442A cells did not differentiate into mature adipocytes in immunodeficient nude mice. Taken together, Snail is a novel regulator of adipocyte differentiation, which acts by direct suppression of PPARγ expression. Our data also indicate that the expression of Snail is mediated by the Wnt–GSK3β signaling pathway.

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Abbreviations

C/EBPα:

CCAAT-enhancer-binding protein alpha

ChIP:

Chromatin immunoprecipitation

EMT:

Epithelial–mesenchymal transition

HDAC:

Histone deacetylase

PPARγ:

Peroxisome proliferator-activated receptor gamma

siRNA:

Small interfering RNA

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Acknowledgments

We sincerely thank Chun Sik Park, MD, PhD, for his critical comments on the study. This study was supported by a faculty research grant of Yonsei University College of Medicine for 2012 (6-2012-2010).Y. L., S. H. K. and Y. J. L. researched data. Y. L., S. H. K. and H. C. L. wrote the manuscript. E. S. K., B–W. L., B. S. C. J. W. K., and D. H. S. contributed to the discussion and reviewed and edited the manuscript. H. C. L. is the guarantor of this work and had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Authors and Affiliations

  1. Department of Internal Medicine, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu, Seoul, 120-752, Korea

    Yong-ho Lee, Soo Hyun Kim, Eun Seok Kang, Byung-Wan Lee, Bong Soo Cha & Hyun Chul Lee

  2. Graduate school, Yonsei University College of Medicine, Seoul, Korea

    Yong-ho Lee, Eun Seok Kang, Byung-Wan Lee, Bong Soo Cha & Hyun Chul Lee

  3. Department of Biochemistry, Yonsei University College of Medicine, Seoul, Korea

    Yoo Jeong Lee & Jae Woo Kim

  4. Department of Pathology, The Armed Forces Capital Hospital, Seongnam, Korea

    Dae Hyun Song

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  1. Yong-ho Lee
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Correspondence to Hyun Chul Lee.

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Yong-ho Lee and Soo Hyun Kim contributed equally to this work and should be considered as the first authors.

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Lee, Yh., Kim, S.H., Lee, Y.J. et al. Transcription factor Snail is a novel regulator of adipocyte differentiation via inhibiting the expression of peroxisome proliferator-activated receptor γ. Cell. Mol. Life Sci. 70, 3959–3971 (2013). https://doi.org/10.1007/s00018-013-1363-8

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