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 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.
authors.affiliation: Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Sara M
authors.initials: SM
authors.lastname: Reyna
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Ghosh
authors.forename: Puntip
authors.initials: P
authors.lastname: Tantiwong
authors.forename: C S Reddy
authors.initials: CS
authors.lastname: Meka
authors.forename: Phyllis
authors.initials: P
authors.lastname: Eagan
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Jenkinson
authors.forename: Eugenio
authors.initials: E
authors.lastname: Cersosimo
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Defronzo
authors.forename: Dawn K
authors.initials: DK
authors.lastname: Coletta
authors.forename: Apiradee
authors.initials: A
authors.lastname: Sriwijitkamol
authors.forename: Nicolas
authors.initials: N
authors.lastname: Musi
mesh_terms: D000328:Adult; D015153:Blotting, Western; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D005230:Fatty Acids, Nonesterified; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D000072000:NF-KappaB Inhibitor alpha