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J. Biol. Chem., Vol. 278, Issue 52, 52298-52306, December 26, 2003

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Expression Profiling Identifies Genes That Continue to Respond to Insulin in Adipocytes Made Insulin-resistant by Treatment with Tumor Necrosis Factor-^*

Peter Sartipy and David J. Loskutoff

From the Department of Cell Biology, Division of Vascular Biology, Scripps Research Institute, La Jolla, California 92037

We have employed microarray technology using RNA from normal 3T3-L1 adipocytes and from 3T3-L1 adipocytes made insulin-resistant by treatment with tumor necrosis factor- to identify a new class of insulin-responsive genes. These genes continued to respond normally to insulin even though the adipocytes themselves were metabolically insulin-resistant, i.e. they displayed a significantly decreased rate of insulin-stimulated glucose uptake. Approximately 12,000 genes/expressed sequence tags (ESTs) were screened. Of these, 40 genes/ESTs were identified that became insulin-resistant as expected (e.g. Socs-3, junB, and matrix metalloproteinase-11). However, 61 genes/ESTs continued to respond normally to insulin. Although some of these genes were previously shown to be regulated by insulin (e.g. Glut-1 and ₃-adrenergic receptor), other novel insulin-sensitive genes were also identified (e.g. Egr-1, epiregulin, Fra-1, and ABCA1). Real-time reverse transcription-PCR analysis confirmed the expression patterns of several of the differentially expressed genes. One gene that remained insulin-sensitive in the insulin-resistant adipocytes is the transcription factor Egr-1. Using an antisense strategy, we show that tissue factor and macrophage colony-stimulating factor, two cardiovascular risk factors, are downstream EGR-1 target genes in the adipocyte. Taken together, these data support the hypothesis that some signaling pathways remain insulin-sensitive in metabolically insulin-resistant adipocytes. These pathways may promote abnormal gene expression in hyperinsulinemic states like obesity and type II diabetes and thus may contribute to pathologies associated with these conditions.

Received for publication, June 29, 2003 , and in revised form, October 3, 2003.

^* This work was supported in part by a grant from Novartis Pharmaceuticals and by National Institutes of Health Grant HL59459 (to D. J. L.). This is Scripps Research Institute Manuscript 15322-CB. 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 primer sequences and references.

Supported by a postdoctoral fellowship from the Henning and Johan Throne-Holst Foundation.

To whom correspondence should be addressed: Dept. of Cell Biology, Div. of Vascular Biology, Scripps Research Inst., 10550 N. Torrey Pines Rd., VB-3, La Jolla, CA 92037. Tel.: 858-784-7125; Fax: 858-784-7353; E-mail: loskutof{at}scripps.edu.

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