Elevated Toll-Like Receptor 4 Expression and Signaling in Muscle From Insulin-Resistant Subjects

• Published in: Diabetes (New York, N.Y.) Vol. 57; no. 10; pp. 2595 - 2602
• Main Authors: Reyna, Sara M., Ghosh, Sangeeta, Tantiwong, Puntip, Meka, C.S. Reddy, Eagan, Phyllis, Jenkinson, Christopher P., Cersosimo, Eugenio, DeFronzo, Ralph A., Coletta, Dawn K., Sriwijitkamol, Apiradee, Musi, Nicolas
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.10.2008
• Subjects: Adult; Biological and medical sciences; Blotting, Western; Cell receptors; Cells, Cultured; Cellular signal transduction; Development and progression; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - physiopathology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty acids; Fatty Acids, Nonesterified - pharmacology; Female; Gene expression; Gene Expression - drug effects; Genetic aspects; Humans; I-kappa B Proteins - metabolism; Insulin resistance; Insulin Resistance - physiology; Male; Medical sciences; Metabolism; Middle Aged; Muscle, Skeletal - cytology; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha; Obesity - genetics; Obesity - metabolism; Obesity - physiopathology; Physiological aspects; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - physiology; Toll-Like Receptor 4 - genetics; Toll-Like Receptor 4 - metabolism; Toll-Like Receptor 4 - physiology; Endocrinopathy; Human; Signal transduction; Pancreatic hormone; Diabetes mellitus; Muscle; Insulin; Biological receptor
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db08-0038

Elevated Toll-Like Receptor 4 Expression and Signaling in Muscle From Insulin-Resistant Subjects Sara M. Reyna 1 2 , Sangeeta Ghosh 1 2 , Puntip Tantiwong 1 2 , C.S. Reddy Meka 1 2 , Phyllis Eagan 2 , Christopher P. Jenkinson 1 , Eugenio Cersosimo 1 2 , Ralph A. DeFronzo 1 2 , Dawn K. Coletta 1 , Apiradee Sriwijitkamol 1 2 and Nicolas Musi 1 2 3 1 Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, Texas 2 Texas Diabetes Institute, San Antonio, Texas 3 Sam and Ann Barshop Institute for Longevity and Aging Studies, San Antonio, Texas Corresponding author: Nicolas Musi, nicolas.musi{at}uhs-sa.com Abstract OBJECTIVE— Tall-like receptor (TLR)4 has been implicated in the pathogenesis of free fatty acid (FFA)-induced insulin resistance by activating inflammatory pathways, including inhibitor of κB (IκB)/nuclear factor κB (NFκB). However, it is not known whether insulin-resistant subjects have abnormal TLR4 signaling. We examined whether insulin-resistant subjects have abnormal TLR4 expression and TLR4-driven (IκB/NFκB) signaling in skeletal muscle. RESEARCH DESIGN AND METHODS— TLR4 gene expression and protein content were measured in muscle biopsies in 7 lean, 8 obese, and 14 type 2 diabetic subjects. A primary human myotube culture system was used to examine whether FFAs stimulate IκB/NFκB via TLR4 and whether FFAs increase TLR4 expression/content in muscle. RESULTS— Obese and type 2 diabetic subjects had significantly elevated TLR4 gene expression and protein content in muscle. TLR4 muscle protein content correlated with the severity of insulin resistance. Obese and type 2 diabetic subjects also had lower IκBα content, an indication of elevated IκB/NFκB signaling. The increase in TLR4 and NFκB signaling was accompanied by elevated expression of the NFκB-regulated genes interleukin (IL)-6 and superoxide dismutase (SOD)2. In primary human myotubes, acute palmitate treatment stimulated IκB/NFκB, and blockade of TLR4 prevented the ability of palmitate to stimulate the IκB/NFκB pathway. Increased TLR4 content and gene expression observed in muscle from insulin-resistant subjects were reproduced by treating myotubes from lean, normal-glucose-tolerant subjects with palmitate. Palmitate also increased IL-6 and SOD2 gene expression, and this effect was prevented by inhibiting NFκB. CONCLUSIONS— Abnormal TLR4 expression and signaling, possibly caused by elevated plasma FFA levels, may contribute to the pathogenesis of insulin resistance in humans. Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 15 July 2008. S.M.R. and S.G. contributed equally to this work. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. 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. Accepted July 8, 2008. Received January 10, 2008. DIABETES