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J. Biol. Chem., Vol. 282, Issue 35, 25445-25452, August 31, 2007

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Role of MAPK Phosphatase-1 in the Induction of Monocyte Chemoattractant Protein-1 during the Course of Adipocyte Hypertrophy^*

Ayaka Ito¹, Takayoshi Suganami, Yoshihiro Miyamoto^¶, Yasunao Yoshimasa^¶, Motohiro Takeya^||, Yasutomi Kamei, and Yoshihiro Ogawa²

From the Department of Molecular Medicine and Metabolism and the Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstitution of Tooth and Bone, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062, Japan, the ^¶Department of Medicine, Division of Atherosclerosis and Diabetes, National Cardiovascular Center Hospital, 5-7-1 Fujishirodai, Suita, Osaka 560-0005, Japan, and the ^||Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan

Monocyte chemoattractant protein-1 (MCP-1), an important chemokine whose expression is increased during the course of obesity, plays a role in macrophage infiltration into obese adipose tissue. This study was designed to elucidate the role of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1) in the induction of MCP-1 during the course of adipocyte hypertrophy. We examined the time course of MKP-1 and MCP-1 mRNA expression and extracellular signal-regulated kinase (ERK) phosphorylation in the adipose tissue from mice rendered mildly obese by a short term high fat diet. We also studied the role of MKP-1 in the induction of MCP-1 in 3T3-L1 adipocytes during the course of adipocyte hypertrophy. MCP-1 mRNA expression was increased, followed by ERK activation and down-regulation of MKP-1, an inducible dual specificity phosphatase to inactivate ERK, in the adipose tissue at the early stage of obesity induced by a short term high fat diet, when macrophages are not infiltrated. Down-regulation of MKP-1 preceded ERK activation and increased production of MCP-1 in 3T3-L1 adipocytes in vitro during the course of adipocyte hypertrophy. Adenovirus-mediated restoration of MKP-1 in hypertrophied 3T3-L1 adipocytes reduced the otherwise increased ERK phosphorylation, thereby leading to the significant reduction of MCP-1 mRNA expression. This study provides evidence that the down-regulation of MKP-1 is critical for increased production of MCP-1 during the course of adipocyte hypertrophy.

Received for publication, February 21, 2007 , and in revised form, June 14, 2007.

^* This work was supported in part by a grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Ministry of Health, Labor, and Welfare of Japan, and research grants from the Astellas Foundation for Research on Metabolic Disorders, Astellas Foundation for Research on Medicinal Resources and The Ichiro Kanehara Foundation. 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 Table S1 and Figs. S1–S5.

¹ Supported by the Tokyo Biochemical Research Foundation.

² To whom correspondence should be addressed: Dept. of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, 2-3-10 Kanda-surugadai, Chiyoda-ku, Tokyo 101-0062, Japan. Tel.: 81-3-5280-8108; Fax: 81-3-5280-8108; E-mail: ogawa.mmm{at}mri.tmd.ac.jp.

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