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J. Biol. Chem., Vol. 281, Issue 42, 31245-31253, October 20, 2006

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Transcription Factor Activating Enhancer-binding Protein-2

A NEGATIVE REGULATOR OF ADIPONECTIN GENE EXPRESSION^*

Kazuhiro Ikeda, Hiroshi Maegawa¹, Satoshi Ugi, Yukari Tao, Yoshihiko Nishio, Shuichi Tsukada, Shiro Maeda, and Atsunori Kashiwagi

From the Division of Endocrinology and Metabolism, Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, 520-2192 Japan and Laboratory for Diabetic Nephropathy, SNP Research Center, The Institute of Physical and Chemical Research, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045 Japan

We previously reported the association between the activating enhancer-binding protein-2 (AP-2) transcription factor gene and type 2 diabetes. This gene is preferentially expressed in adipose tissue, and subjects with the disease-susceptible allele of AP-2 showed stronger expression in adipose tissue than those without the susceptible allele. Furthermore, overexpression of AP-2 leads to lipid accumulation by enhancing glucose transport and inducing insulin resistance in 3T3-L1 adipocytes. In this study we demonstrated that overexpression of AP-2 in 3T3-L1 adipocytes decreased the expression and secretion of adiponectin and increased those of interleukin-6 (IL-6). Interestingly, the effects of AP-2 on the expressions of adiponectin and IL-6 and the mechanisms by which AP-2 modulated their expressions were different. We found that the promoter activity of adiponectin gene was inhibited by AP-2 overexpression and enhanced by knockdown of endogenous AP-2, whereas IL-6 was unaffected. Electrophoretic mobility shift assays revealed the existence of putative responsive elements for AP-2 and NF-YA in human and mouse adiponectin promoter regions, and mutation of this AP-2 binding site abolished the inhibitory effect of AP-2. Furthermore, chromatin immunoprecipitation assays demonstrated that AP-2 and NF-YA competitively bind to the same region of the adiponectin promoter. Our results clearly demonstrated that AP-2 directly inhibits adiponectin gene expression by displacing NF-YA and binding to its promoter. We conclude that AP-2 might modulate the expression of adiponectin by directly inhibiting its transcriptional activity.

Received for publication, May 30, 2006 , and in revised form, August 4, 2006.

^* This work was supported in part by a grant-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (to H. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 81-77-548-2222; Fax: 81-77-543-3858; E-mail: maegawa{at}belle.shiga-med.ac.jp.

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