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Transcription Suppression of Peroxisome Proliferator-Activated Receptor 2 Gene Expression by Tumor Necrosis Factor via an Inhibition of CCAAT/ Enhancer-binding Protein during the Early Stage of Adipocyte Differentiation

Division of Nephrology, Endocrinology and Vascular Medicine, Department of Medicine, Tohoku University Graduate School of Medicine, Sendai, 980-8574 Japan

Address all correspondence and requests for reprints to: Akira Sugawara, M.D., Ph.D., Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine, 1-1, Seiryo-cho, Aoba-ku, Sendai, 980-8574 Japan. E-mail: akiras2i{at}mail.tains.tohoku.ac.jp.

TNF is known to inhibit adipocyte differentiation and induce insulin resistance. Moreover, TNF is known to down-regulate peroxisome proliferator-activated receptor (PPAR)2, an adipocyte-specific nuclear receptor of insulin-sensitizer thiazolidinediones. To clarify molecular mechanisms of TNF- mediated PPAR2 down-regulation, we here examined the effect of TNF on transcription regulation of PPAR2 gene expression during the early stage of adipocyte differentiation. 3T3-L1 preadipocytes (2 d after 100% confluent) were incubated in a differentiation mixture (dexamethasone, insulin, 3-isobutyl-1-methlxanthine), with or without 50 ng/ml TNF, for 24 h. TNF significantly decreased PPAR2 expression both at mRNA and protein levels (to 40%), as well as aP2 mRNA expression. The mouse PPAR2 gene promoter region (2.2-kb) was isolated and was used for luciferase reporter assays by transient transfection. TNF significantly suppressed PPAR2 gene transcription (to 50%), and deletion analyses demonstrated that the suppression was mediated via CCAAT/enhancer-binding protein (C/EBP) binding elements at the –320/–340 region of the promoter. Moreover, TNF significantly decreased expression of C/EBP mRNA and protein levels (to 40%). EMSA, using 3T3-L1 cells nuclear extracts with the –320/–340 region as a probe, demonstrated the binding of C/EBP to the element, which was significantly decreased by TNF treatment. Overexpression of CEBP/ prevented the TNF-mediated suppression of PPAR2 transactivation. Taken together, TNF suppresses PPAR2 gene transcription by the inhibition of C/EBP expression and its DNA binding during the early stage of adipocyte differentiation, which may contribute to the inhibition of adipocyte differentiation, as well as the induction of insulin resistance.

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