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Journal of Lipid Research, Vol. 44, 1174-1181, June 2003
Copyright © 2003 by Lipid Research, Inc.

Increased expression of the SNARE accessory protein Munc18c in lipid-mediated insulin resistance

Isabel R. Schlaepfer^*, Leslie K. Pulawa^*, Luis D. M. C-B. Ferreira^1,*, David E. James^2,, Warren H. Capell^* and Robert H. Eckel^3,*

^* Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Colorado Health Sciences Center, Denver, CO 80262
Institute for Molecular Bioscience, University of Queensland, St. Lucia, Qld 4072, Australia

³ To whom correspondence should be addressed. e-mail: robert.eckel{at}uchsc.edu

Fatty acids inhibit insulin-mediated glucose metabolism in skeletal muscle, an effect largely attributed to defects in insulin-mediated glucose transport. Insulin-resistant mice transgenic for the overexpression of lipoprotein lipase (LPL) in skeletal muscle were used to examine the molecular mechanism(s) in more detail. Using DNA gene chip array technology, and confirmation by RT-PCR and Western analysis, increases in the yeast Sec1p homolog Munc18c mRNA and protein were found in the gastrocnemius muscle of transgenic mice, but not other tissues. Munc18c has been previously demonstrated to impair insulin-mediated glucose transport in mammalian cells in vitro. Of interest, stably transfected C2C12 cells overexpressing LPL not only demonstrated increases in Munc18c mRNA and protein but also in transcription rates of the Munc18c gene.

To confirm the relevance of fatty acid metabolism and insulin resistance to the expression of Munc18c in vivo, a 2-fold increase in Munc18c protein was demonstrated in mice fed a high-fat diet for 4 weeks. Together, these data are the first to implicate in vivo increases in Munc18c as a potential contributing mechanism to fatty acid-induced insulin resistance.

Abbreviations: EST, expressed sequence tag; DGAT, diacylglycerol acyltransferase; PI 3-kinase, phosphatidylinositol 3-kinase; SNARE, soluble N-ethylmaleimide-sensitive factor attachment protein receptor

Supplementary key words GLUT4 • muscle • soluble N-ethylmaleimide-sensitive factor attachment protein receptor

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