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

226 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 2008
Externally publishedYes

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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, 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;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.
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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.",
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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

Y1 - 2008/10

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.

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