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J. Biol. Chem., Vol. 278, Issue 23, 20906-20914, June 6, 2003

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Insulin-like Growth Factor-1/Insulin Bypasses Pref-1/FA1-mediated Inhibition of Adipocyte Differentiation^*

Hongbin Zhang , Jane Nøhr , Charlotte H. Jensen , Rasmus K. Petersen , Elin Bachmann , Børge Teisner , Leif K. Larsen ¶, Susanne Mandrup  and Karsten Kristiansen  ||

From the Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, 5230 Odense M., the Department of Immunology and Microbiology, University of Southern Denmark, Winsløvsparken 21-1, 5000 Odense C., and ^¶Rheoscience, Glerupvej 2, DK-2610 Rødovre, Denmark

Pref-1 is a highly glycosylated Delta-like transmembrane protein containing six epidermal growth factor-like repeats in the extracellular domain. Pref-1 is abundantly expressed in preadipocytes, but expression is down-regulated during adipocyte differentiation. Forced expression of Pref-1 in 3T3-L1 cells was reported to inhibit adipocyte differentiation. Here we show that efficient and regulated processing of Pref-1 occurs in 3T3-L1 preadipocytes releasing most of the extracellular domain as a 50-kDa heterogeneous protein, previously isolated and characterized as FA1. Unexpectedly, we found that forced expression of the soluble form, FA1, or full-length Pref-1 did not inhibit adipocyte differentiation of 3T3-L1 cells when differentiation was induced by standard treatment with methylisobutylxanthine, dexamethasone, and high concentrations of insulin. However, forced expression of either form of Pref-1/FA1 in 3T3-L1 or 3T3-F442A cells inhibited adipocyte differentiation when insulin or insulin-like growth factor-1 (IGF-1) was omitted from the differentiation mixture. We demonstrate that the level of the mature form of the IGF-1 receptor is reduced and that IGF-1-dependent activation of p42/p44 mitogen-activated protein kinases (MAPKs) is compromised in preadipocytes with forced expression of Pref-1. This is accompanied by suppression of clonal expansion and terminal differentiation. Accordingly, supplementation with insulin or IGF-1 rescued p42/p44 MAPK activation, clonal expansion, and adipocyte differentiation in a dose-dependent manner.

Received for publication, January 2, 2003 , and in revised form, March 20, 2003.

^* This work was supported by the Danish Biotechnology Program, the Danish Natural Science Research Council, the Danish Medical Research Council, the Daloon Foundation, and the Novo Nordisk Foundation. Part of the work was conducted within the Center for Experimental BioInformatics, supported by the Danish National Research 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.

^|| To whom correspondence should be addressed. Tel.: 45-6550-2408; Fax: 45-6550-2467; E-mail: kak{at}bmb.sdu.dk.

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