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J. Biol. Chem., Vol. 281, Issue 49, 37913-37920, December 8, 2006

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Oncostatin M Inhibits Adipogenesis through the RAS/ERK and STAT5 Signaling Pathways^*

Yuichiro Miyaoka¹, Minoru Tanaka, Takahiro Naiki, and Atsushi Miyajima²

From the Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan and the Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), Kawaguchi, Saitama 332-0012, Japan

Adipocytes play a key role in energy homeostasis and several cytokines have been shown to regulate adipogenesis. While the interleukin (IL)-6 family of cytokines was previously reported to be involved in adipogenesis, roles of this family in adipogenesis and their mechanisms of action are not fully understood. Here we show that among the IL-6 family, oncostatin M (OSM) most strongly inhibits adipogenesis of 3T3-L1 cells and mouse embryonic fibroblasts (MEFs). We also demonstrate that OSM inhibits adipogenesis through the Ras/extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription (STAT) 5 signaling pathways. In addition, OSM inhibits the early phase of the differentiation without affecting cell proliferation throughout adipogenesis including mitotic clonal expansion. CCAAT/enhancer-binding protein (C/EBP) , C/EBP, and peroxisome proliferator-activated receptor (PPAR) are known to be required for adipogenesis. Expression of C/EBP and PPAR was almost completely abrogated by OSM. In contrast, neither the mRNA nor protein level of C/EBP was affected by OSM. Forced expression of C/EBP induced differentiation in the presence of troglitazone, and OSM inhibited this C/EBP-induced differentiation. Taken together, our results indicate that OSM inhibits the onset of terminal differentiation of adipocytes through the Ras/ERK and STAT5 signaling pathways by possibly regulating C/EBP activity.

Received for publication, June 26, 2006 , and in revised form, October 5, 2006.

^* This work was supported in part by grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and from the CREST program of JST. 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 Recipient of a JSPS Research Fellowship for Young Scientists.

² To whom correspondence should be addressed: Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. Tel.: 81-3-5841-7884; Fax: 81-3-5841-8475; E-mail: miyajima{at}iam.u-tokyo.ac.jp.

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