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

Reyna SM, Ghosh S, Tantiwong P, Meka CS, Eagan P, Jenkinson CP, Cersosimo E, Defronzo RA, Coletta DK, Sriwijitkamol A, Musi N - Diabetes (2008)

Bottom Line: The increase in TLR4 and NFkappaB signaling was accompanied by elevated expression of the NFkappaB-regulated genes interleukin (IL)-6 and superoxide dismutase (SOD)2.In primary human myotubes, acute palmitate treatment stimulated IkappaB/NFkappaB, and blockade of TLR4 prevented the ability of palmitate to stimulate the IkappaB/NFkappaB pathway.Palmitate also increased IL-6 and SOD2 gene expression, and this effect was prevented by inhibiting NFkappaB.

View Article: PubMed Central - PubMed

Affiliation: Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.

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 kappaB (IkappaB)/nuclear factor kappaB (NFkappaB). 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 (IkappaB/NFkappaB) 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 IkappaB/NFkappaB 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 IkappaBalpha content, an indication of elevated IkappaB/NFkappaB signaling. The increase in TLR4 and NFkappaB signaling was accompanied by elevated expression of the NFkappaB-regulated genes interleukin (IL)-6 and superoxide dismutase (SOD)2. In primary human myotubes, acute palmitate treatment stimulated IkappaB/NFkappaB, and blockade of TLR4 prevented the ability of palmitate to stimulate the IkappaB/NFkappaB 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 NFkappaB. 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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TLR4 signaling. IκBα protein abundance (A) and mRNA expression of IL-6 (B) and SOD2 (C) were measured in lean, obese, and type 2 diabetic (T2DM) subjects. Data are means ± SE. *P < 0.05; †P = 0.05 vs. lean.
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f2: TLR4 signaling. IκBα protein abundance (A) and mRNA expression of IL-6 (B) and SOD2 (C) were measured in lean, obese, and type 2 diabetic (T2DM) subjects. Data are means ± SE. *P < 0.05; †P = 0.05 vs. lean.

Mentions: We examined whether increased TLR4 gene expression and protein content in insulin-resistant subjects was associated with abnormal TLR4 signaling by measuring abundance of IκBα. Obese and type 2 diabetic subjects had decreased IκBα content in muscle (Fig. 2A). Because phosphorylation of IκB by IKK leads to IκB degradation, a reduction in IκB abundance is considered to indicate activation of the IκB/NFκB pathway (31). IκB abundance inversely correlated with fasting plasma FFA concentrations (r = −0.6, P = 0.005) and FFA AUC during OGTT (r = −0.46, P = 0.03) and tended to correlate negatively with the HOMA index (r = −0.34, P = 0.1). Currently, we are investigating whether direct measurement of IKK activity (which was not measured because of insufficient protein) has a stronger (negative) correlation with insulin sensitivity measured with the insulin clamp.


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

Reyna SM, Ghosh S, Tantiwong P, Meka CS, Eagan P, Jenkinson CP, Cersosimo E, Defronzo RA, Coletta DK, Sriwijitkamol A, Musi N - Diabetes (2008)

TLR4 signaling. IκBα protein abundance (A) and mRNA expression of IL-6 (B) and SOD2 (C) were measured in lean, obese, and type 2 diabetic (T2DM) subjects. Data are means ± SE. *P < 0.05; †P = 0.05 vs. lean.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2551667&req=5

f2: TLR4 signaling. IκBα protein abundance (A) and mRNA expression of IL-6 (B) and SOD2 (C) were measured in lean, obese, and type 2 diabetic (T2DM) subjects. Data are means ± SE. *P < 0.05; †P = 0.05 vs. lean.
Mentions: We examined whether increased TLR4 gene expression and protein content in insulin-resistant subjects was associated with abnormal TLR4 signaling by measuring abundance of IκBα. Obese and type 2 diabetic subjects had decreased IκBα content in muscle (Fig. 2A). Because phosphorylation of IκB by IKK leads to IκB degradation, a reduction in IκB abundance is considered to indicate activation of the IκB/NFκB pathway (31). IκB abundance inversely correlated with fasting plasma FFA concentrations (r = −0.6, P = 0.005) and FFA AUC during OGTT (r = −0.46, P = 0.03) and tended to correlate negatively with the HOMA index (r = −0.34, P = 0.1). Currently, we are investigating whether direct measurement of IKK activity (which was not measured because of insufficient protein) has a stronger (negative) correlation with insulin sensitivity measured with the insulin clamp.

Bottom Line: The increase in TLR4 and NFkappaB signaling was accompanied by elevated expression of the NFkappaB-regulated genes interleukin (IL)-6 and superoxide dismutase (SOD)2.In primary human myotubes, acute palmitate treatment stimulated IkappaB/NFkappaB, and blockade of TLR4 prevented the ability of palmitate to stimulate the IkappaB/NFkappaB pathway.Palmitate also increased IL-6 and SOD2 gene expression, and this effect was prevented by inhibiting NFkappaB.

View Article: PubMed Central - PubMed

Affiliation: Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.

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 kappaB (IkappaB)/nuclear factor kappaB (NFkappaB). 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 (IkappaB/NFkappaB) 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 IkappaB/NFkappaB 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 IkappaBalpha content, an indication of elevated IkappaB/NFkappaB signaling. The increase in TLR4 and NFkappaB signaling was accompanied by elevated expression of the NFkappaB-regulated genes interleukin (IL)-6 and superoxide dismutase (SOD)2. In primary human myotubes, acute palmitate treatment stimulated IkappaB/NFkappaB, and blockade of TLR4 prevented the ability of palmitate to stimulate the IkappaB/NFkappaB 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 NFkappaB. CONCLUSIONS- Abnormal TLR4 expression and signaling, possibly caused by elevated plasma FFA levels, may contribute to the pathogenesis of insulin resistance in humans.

Show MeSH
Related in: MedlinePlus