Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects

Sara M. Reyna, Sangeeta Ghosh, Puntip Tantiwong, C. S.Reddy Meka Meka, Phyllis Eagan, Christopher P. Jenkinson, Eugenio Cersosimo, Ralph A. Defronzo, Dawn K. Coletta, Apiradee Sriwijitkamol, Nicolas Musi

Research output: Contribution to journalArticle

233 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2595-2602
Number of pages8
JournalDiabetes
Volume57
Issue number10
DOIs
StatePublished - Oct 1 2008
Externally publishedYes

Fingerprint

Toll-Like Receptor 4
Palmitates
Insulin
Muscles
Skeletal Muscle Fibers
Insulin Resistance
Gene Expression
Nonesterified Fatty Acids
Interleukin-6
Muscle Proteins
3'-(1-butylphosphoryl)adenosine
Skeletal Muscle
Proteins
Research Design
Biopsy
Glucose
Genes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Reyna, S. M., Ghosh, S., Tantiwong, P., Meka, C. S. R. M., Eagan, P., Jenkinson, C. P., ... Musi, N. (2008). Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects. Diabetes, 57(10), 2595-2602. https://doi.org/10.2337/db08-0038

Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects. / Reyna, Sara M.; Ghosh, Sangeeta; Tantiwong, Puntip; Meka, C. S.Reddy Meka; Eagan, Phyllis; Jenkinson, Christopher P.; Cersosimo, Eugenio; Defronzo, Ralph A.; Coletta, Dawn K.; Sriwijitkamol, Apiradee; Musi, Nicolas.

In: Diabetes, Vol. 57, No. 10, 01.10.2008, p. 2595-2602.

Research output: Contribution to journalArticle

Reyna, SM, Ghosh, S, Tantiwong, P, Meka, CSRM, Eagan, P, Jenkinson, CP, Cersosimo, E, Defronzo, RA, Coletta, DK, Sriwijitkamol, A & Musi, N 2008, 'Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects', Diabetes, vol. 57, no. 10, pp. 2595-2602. https://doi.org/10.2337/db08-0038
Reyna SM, Ghosh S, Tantiwong P, Meka CSRM, Eagan P, Jenkinson CP et al. Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects. Diabetes. 2008 Oct 1;57(10):2595-2602. https://doi.org/10.2337/db08-0038
Reyna, Sara M. ; Ghosh, Sangeeta ; Tantiwong, Puntip ; Meka, C. S.Reddy Meka ; Eagan, Phyllis ; Jenkinson, Christopher P. ; Cersosimo, Eugenio ; Defronzo, Ralph A. ; Coletta, Dawn K. ; Sriwijitkamol, Apiradee ; Musi, Nicolas. / Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects. In: Diabetes. 2008 ; Vol. 57, No. 10. pp. 2595-2602.
@article{816fd8b6c67442b184d471531475b7e4,
title = "Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects",
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.",
author = "Reyna, {Sara M.} and Sangeeta Ghosh and Puntip Tantiwong and Meka, {C. S.Reddy Meka} and Phyllis Eagan and Jenkinson, {Christopher P.} and Eugenio Cersosimo and Defronzo, {Ralph A.} and Coletta, {Dawn K.} and Apiradee Sriwijitkamol and Nicolas Musi",
year = "2008",
month = "10",
day = "1",
doi = "10.2337/db08-0038",
language = "English (US)",
volume = "57",
pages = "2595--2602",
journal = "Diabetes",
issn = "0012-1797",
publisher = "American Diabetes Association Inc.",
number = "10",

}

TY - JOUR

T1 - Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects

AU - Reyna, Sara M.

AU - Ghosh, Sangeeta

AU - Tantiwong, Puntip

AU - Meka, C. S.Reddy Meka

AU - Eagan, Phyllis

AU - Jenkinson, Christopher P.

AU - Cersosimo, Eugenio

AU - Defronzo, Ralph A.

AU - Coletta, Dawn K.

AU - Sriwijitkamol, Apiradee

AU - Musi, Nicolas

PY - 2008/10/1

Y1 - 2008/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=58149359307&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=58149359307&partnerID=8YFLogxK

U2 - 10.2337/db08-0038

DO - 10.2337/db08-0038

M3 - Article

C2 - 18633101

AN - SCOPUS:58149359307

VL - 57

SP - 2595

EP - 2602

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 10

ER -