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J. Biol. Chem., Vol. 280, Issue 51, 42016-42025, December 23, 2005

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Resistin-like Molecule Activates MAPKs, Suppresses Insulin Signaling in Hepatocytes, and Induces Diabetes, Hyperlipidemia, and Fatty Liver in Transgenic Mice on a High Fat Diet^*

Akifumi Kushiyama, Nobuhiro Shojima, Takehide Ogihara, Kouichi Inukai¶, Hideyuki Sakoda, Midori Fujishiro, Yasushi Fukushima, Motonobu Anai||, Hiraku Ono||, Nanao Horike**, Amelia Y. I. Viana**, Yasunobu Uchijima**, Koichi Nishiyama**, Tatsuo Shimosawa, Toshiro Fujita, Hideki Katagiri, Yoshitomo Oka, Hiroki Kurihara**, and Tomoichiro Asano**1

From the Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, the Division of Advanced Therapeutics for Metabolic Diseases, Center for Translational and Advanced Animal Research on Human Diseases, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Sendai, Miyagi 980-8574, the ^¶Division of Endocrinology and Diabetes, Department of Medicine, Saitama Medical School, Morohongo 38, Moroyama, Iruma-gun, Saitama 350-0495, the ^||Department of Internal Medicine, Institute for Adult Diseases, Asahi Life Foundation, 1-6-1, Marunouchi, Chiyodaku, Tokyo 100-0005, and the ^**Department of Physiological Chemistry and Metabolism, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan

Resistin and resistin-like molecules (RELMs) are a family of proteins reportedly related to insulin resistance and inflammation. Because the serum concentration and intestinal expression level of RELM were elevated in insulin-resistant rodent models, in this study we investigated the effect of RELM on insulin signaling and metabolism using transgenic mice and primary cultured hepatocytes. First, transgenic mice with hepatic RELM overexpression were shown to exhibit significant hyperglycemia, hyperlipidemia, fatty liver, and pancreatic islet enlargement when fed a high fat diet. Hyperinsulinemic glucose clamp showed a decreased glucose infusion rate due to increased hepatic glucose production. In addition, the expression levels of IRS-1 and IRS-2 proteins as well as the degrees of insulin-induced phosphatidylinositol 3-kinase and Akt activations were attenuated in RELM transgenic mice. Similar down-regulations of IRS-1 and IRS-2 proteins were observed in primary cultured hepatocytes chronically treated (for 24 h) with RELM, suggesting the insulin resistance-inducing effect of RELM to be direct. Furthermore, it was shown that RELM acutely and markedly activates ERK and p38, while weakly activating JNK, in primary cultured hepatocytes. This increased basal p38 phosphorylation level was also observed in the livers of RELM transgenic mice. In conclusion, RELM, a gut-derived hormone, impairs insulin signaling probably via the activations of classic MAPKs, and increased expression of RELM may be involved in the pathogenesis of glucose intolerance and hyperlipidemia in some insulin-resistant models. Thus, RELM is a potentially useful marker for assessing insulin resistance and may also be a target for future novel anti-diabetic agents.

Received for publication, March 21, 2005 , and in revised form, October 18, 2005.

^* 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.: 81-3-5841-3603; Fax: 81-3-5803-1874; E-mail: asano-tky{at}umin.ac.jp.

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