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J. Biol. Chem., Vol. 282, Issue 42, 30794-30803, October 19, 2007

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Disruption of CXC Motif Chemokine Ligand-14 in Mice Ameliorates Obesity-induced Insulin Resistance^*

Noriko Nara¹², Yuki Nakayama¹, Shiki Okamoto, Hiroshi Tamura, Mari Kiyono, Masatoshi Muraoka, Kiyoko Tanaka, Choji Taya^¶, Hiroshi Shitara^¶, Rie Ishii^¶, Hiromichi Yonekawa^¶, Yasuhiko Minokoshi, and Takahiko Hara³

From the Stem Cell Project Group and the ^¶Laboratory of Mouse Model for Human Heritable Diseases, Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Organization for Medical Research, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613 and the Division of Endocrinology and Metabolism, National Institute for Physiological Sciences, 38 Nishigonaka Myodaiji, Okazaki, Aichi 444-8585, Japan

In obese individuals, white adipose tissue (WAT) is infiltrated by large numbers of macrophages, resulting in enhanced inflammatory responses that contribute to insulin resistance. Here we show that expression of the CXC motif chemokine ligand-14 (CXCL14), which targets tissue macrophages, is elevated in WAT of obese mice fed a high fat diet (HFD) compared with lean mice fed a regular diet. We found that HFD-fed CXCL14-deficient mice have impaired WAT macrophage mobilization and improved insulin responsiveness. Insulin-stimulated phosphorylation of Akt kinase in skeletal muscle was severely attenuated in HFD-fed CXCL14^+/- mice but not in HFD-fed CXCL14^-/- mice. The insulin-sensitive phenotype of CXCL14^-/- mice after HFD feeding was prominent in female mice but not in male mice. HFD-fed CXCL14^-/- mice were protected from hyperglycemia, hyperinsulinemia, and hypoadiponectinemia and did not exhibit increased levels of circulating retinol-binding protein-4 and increased expression of interleukin-6 in WAT. Transgenic overexpression of CXCL14 in skeletal muscle restored obesity-induced insulin resistance in CXCL14^-/- mice. CXCL14 attenuated insulin-stimulated glucose uptake in cultured myocytes and to a lesser extent in cultured adipocytes. These results demonstrate that CXCL14 is a critical chemoattractant of WAT macrophages and a novel regulator of glucose metabolism that functions mainly in skeletal muscle.

Received for publication, January 16, 2007 , and in revised form, July 13, 2007.

^* This work was supported in part by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to Y. N. and T. H.) and a grant-in-aid for research on nervous and mental disorders from the Ministry of Health, Labor and Welfare of Japan (to T. H.). 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 Figs. S1-S6 and Table S1.

¹ Both authors contributed equally to this work.

² Recipient of a research fellowship from the Japanese Society for the Promotion of Science.

³ To whom correspondence should be addressed. Tel.: 81-3-4463-7595; Fax: 81-3-3823-1418; E-mail: thara{at}rinshoken.or.jp.

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