Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates
- *Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California at San Diego, 9500 Gilman Drive, MC 0723, La Jolla, CA 92093-0723;
- †Department of Biomedical Sciences/Instituto Nazionale di Biostrutture e Biosistemi, University of Sassari Medical School, 07100 Sassari, Italy; and
- ‡Department of Medicine, Samsung Medical Center, 50 Irwon-dong Kangnam-ku, Seoul 135-710, Korea
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Contributed by Michael Karin, September 1, 2006
Abstract
JNKs are attractive targets for treatment of obesity and type-2 diabetes. A sustained increase in JNK activity was observed in dietary and genetic models of obesity in mice, whereas JNK deficiency prevented obesity-induced insulin resistance. A similar insulin-sensitizing effect was seen upon treatment of obese mice with JNK inhibitors. We now demonstrate that treatment with the saturated fatty acid palmitic acid results in sustained JNK activation and insulin resistance in primary mouse hepatocytes and pancreatic β-cells. In the latter, palmitic acid treatment inhibits glucose-induced insulin gene transcription, in part, by interfering with autocrine insulin signaling through phosphorylation of insulin-receptor substrates 1 and 2 at sites that interfere with binding to activated insulin receptors. This mechanism may account for the induction of central insulin resistance by free fatty acids.
Footnotes
- §To whom correspondence should be addressed. E-mail: karinoffice{at}ucsd.edu
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Author contributions: G.S. and M.K. designed research; G.S. and W.N. performed research; G.S., W.N., F.G., and M.-S.L. contributed new reagents/analytic tools; G.S. and M.K. analyzed data; and G.S. and M.K. wrote the paper.
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The authors declare no conflict of interest.
- Abbreviations:
- D-JNKi,
- JNK-inhibitory peptide;
- FFA,
- free fatty acid(s);
- InsR,
- insulin receptor;
- IRS,
- InsR substrate;
- PA,
- palmitic acid;
- PTB,
- phosphotyrosine-binding motif.
- © 2006 by The National Academy of Sciences of the USA
