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Gastroenterology Research and Practice
Volume 2010 (2010), Article ID 212563, 11 pages
Review Article

TLR4 and Insulin Resistance

1Department of Pediatrics, University of California, San Diego, CA 92093-0673, USA
2Rady Children's Hospital, San Diego, CA 92093-0673, USA
3Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0673, USA

Received 21 April 2010; Accepted 24 June 2010

Academic Editor: Ekihiro Seki

Copyright © 2010 Jane J. Kim and Dorothy D. Sears. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Chronic inflammation is a key feature of insulin resistance and obesity. Toll-Like Receptor 4 (TLR4), involved in modulating innate immunity, is an important mediator of insulin resistance and its comorbidities. TLR4 contributes to the development of insulin resistance and inflammation through its activation by elevated exogenous ligands (e.g., dietary fatty acids and enteric lipopolysaccharide) and endogenous ligands (e.g., free fatty acids) which are elevated in obese states. TLR4, expressed in insulin target tissues, activates proinflammatory kinases JNK, IKK, and p38 that impair insulin signal transduction directly through inhibitory phosphorylation of insulin receptor substrate (IRS) on serine residues. TLR4 activation also leads to increased transcription of pro-inflammatory genes, resulting in elevation of cytokine, chemokine, reactive oxygen species, and eicosanoid levels that promote further insulin-desensitization within the target cell itself and in other cells via paracrine and systemic effects. Increased understanding of cell type-specific TLR4-mediated effects on insulin action present the opportunity and challenge of developing related therapeutic approaches for improving insulin sensitivity while preserving innate immunity.