Increased expression of the SNARE accessory protein Munc18c in lipid-mediated insulin resistance.
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.
Schlaepfer
Isabel R
IR
Department of Medicine, Division of Endocrinology, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Pulawa
Leslie K
LK
Ferreira
Luis D M C-B
LD
James
David E
DE
Capell
Warren H
WH
Eckel
Robert H
RH
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D004041:Dietary Fats / Q000008:administration & dosage; D007333:Insulin Resistance / Q000235:genetics*; D050356:Lipid Metabolism; D008071:Lipoprotein Lipase / Q000096:biosynthesis / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D051938:Munc18 Proteins; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050600:SNARE Proteins; D014162:Transfection; D033921:Vesicular Transport Proteins
D001786:Blood Glucose; D004041:Dietary Fats; D008565:Membrane Proteins; D051938:Munc18 Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D050600:SNARE Proteins; C497943:Stxbp3 protein, mouse; D033921:Vesicular Transport Proteins; D008071:Lipoprotein Lipase