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J. Biol. Chem., Vol. 280, Issue 45, 37669-37680, November 11, 2005

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SOX6 Attenuates Glucose-stimulated Insulin Secretion by Repressing PDX1 Transcriptional Actvity and Is Down-regulated in Hyperinsulinemic Obese Mice^*

Haruhisa Iguchi1, Yukio Ikeda, Masashi Okamura, Toshiya Tanaka, Yasuyo Urashima, Hiroto Ohguchi, Shinobu Takayasu, Noriaki Kojima, Satoshi Iwasaki, Riuko Ohashi£, Shuying Jiang£, Go Hasegawa£, Ryoichi X. Ioka, Kenta Magoori, Koichi Sumi, Takashi Maejima, Aoi Uchida, Makoto Naito£, Timothy F. Osborne||, Masashi Yanagisawa**2, Tokuo T. Yamamoto, Tatsuhiko Kodama, and Juro Sakai3

From the Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan, Yanagisawa Orphan Receptor Project, Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Tokyo 135-0064, Japan, the ^£Department of Cellular Function, Division of Cellular and Molecular Pathology, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8510, Japan, the ^||Department of Molecular Biology and Biochemistry, University of California, Irvine, California 92717-3900, ^**Howard Hughes Medical Institute and Department of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9050, and Center for Advanced Genome Research, Institute of Development, Aging and Cancer, Tohoku University, Sendai 981-8555, Japan

In obesity-related insulin resistance, pancreatic islets compensate for insulin resistance by increasing secretory capacity. Here, we report the identification of sex-determining region Y-box 6 (SOX6), a member of the high mobility group box superfamily of transcription factors, as a co-repressor for pancreatic-duodenal homeobox factor-1 (PDX1). SOX6 mRNA levels were profoundly reduced by both a long term high fat feeding protocol in normal mice and in genetically obese ob/ob mice on a normal chow diet. Interestingly, we show that SOX6 is expressed in adult pancreatic insulin-producing -cells and that overexpression of SOX6 decreased glucose-stimulated insulin secretion, which was accompanied by decreased ATP/ADP ratio, Ca²⁺ mobilization, proinsulin content, and insulin gene expression. In a complementary fashion, depletion of SOX6 by small interfering RNAs augmented glucose-stimulated insulin secretion in insulinoma mouse MIN6 and rat INS-1E cells. These effects can be explained by our mechanistic studies that show SOX6 acts to suppress PDX1 stimulation of the insulin II promoter through a direct protein/protein interaction. Furthermore, SOX6 retroviral expression decreased acetylation of histones H3 and H4 in chromatin from the promoter for the insulin II gene, suggesting that SOX6 may decrease PDX1 stimulation through changes in chromatin structure at specific promoters. These results suggest that perturbations in transcriptional regulation that are coordinated through SOX6 and PDX1 in -cells may contribute to the -cell adaptation in obesity-related insulin resistance.

Received for publication, May 17, 2005 , and in revised form, August 29, 2005.

^* This work was supported in part by research grants from the Ministry of Education, Science, and Culture of Japan, Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sports, Science, and Technology of the Japanese Government, Astellas Foundation for Research on Metabolic Disorders, Research Fund of Mitsukoshi Health and Welfare Foundation, and Exploratory Research for Advanced Technology/Japan Science and Technology Agency (Yanagisawa orphan receptor project). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1 and Table 1.

¹ Present address: Genomics Science Laboratories, Sumitomo Pharmaceuticals Co. Ltd., Takarazuka 665-0051, Japan.

² An Investigator of the Howard Hughes Medical Institute.

³ To whom correspondence should be addressed: Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan. Tel.: 81-3-5452-5472; Fax: 81-3-5452-5429; E-mail: jmsakai-tky{at}umin.ac.jp.

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