title: A sustained increase in plasma NEFA upregulates the Toll-like receptor network in human muscle.
abstract: OBJECTIVE
  Insulin-sensitive tissues (muscle, liver) of individuals with obesity and type 2 diabetes mellitus are in a state of low-grade inflammation, characterised by increased Toll-like receptor (TLR) expression and TLR-driven signalling. However, the cause of this mild inflammatory state is unclear. We tested the hypothesis that a prolonged mild increase in plasma NEFA will increase TLR expression and TLR-driven signalling (nuclear factor κB [NFκB] and mitogen-activated kinase [MAPK]) and impair insulin action in muscle of lean healthy individuals.
  
  
  METHODS
  Twelve lean, normal-glucose-tolerant participants were randomised to receive a 48 h infusion (30 ml/h) of saline or Intralipid followed by a euglycaemic-hyperinsulinaemic clamp. Vastus lateralis muscle biopsies were performed before and during the clamp.
  
  
  RESULTS
  Lipid infusion impaired insulin-stimulated IRS-1 tyrosine phosphorylation and reduced peripheral insulin sensitivity (p < 0.01). The elevation in circulating NEFA increased expression of TLR3, TLR4 and TLR5, and several MAPK (MAPK8, MAP4K4, MAP2K3) and inhibitor of κB kinase-NFκB (CHUK [IKKA], c-REL [REL] and p65 [RELA, NFKB3, p65]) signalling genes (p < 0.05). The lipid infusion also increased extracellular signal-regulated kinase (ERK) phosphorylation (p < 0.05) and tended to reduce the content of inhibitor of kappa Bα (p = 0.09). The muscle content of most diacylglycerol, ceramide and acylcarnitine species was unaffected. In summary, insulin resistance induced by prolonged low-dose lipid infusion occurs together with increased TLR-driven inflammatory signalling and impaired insulin-stimulated IRS-1 tyrosine phosphorylation.
  
  
  CONCLUSIONS
  A sustained, mild elevation in plasma NEFA is sufficient to increase TLR expression and TLR-driven signalling (NFκB and MAPK) in lean individuals. The activation of this pathway by NEFA may be involved in the pathogenesis of insulin resistance in humans.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT01740817.
authors: Department of Medicine-Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
authors: Sophie E
authors: SE
authors: Hussey
authors: Helen
authors: H
authors: Lum
authors: Andrea
authors: A
authors: Alvarez
authors: Yolanda
authors: Y
authors: Cipriani
authors: Jesús
authors: J
authors: Garduño-Garcia
authors: Luis
authors: L
authors: Anaya
authors: John
authors: J
authors: Dube
authors: Nicolas
authors: N
authors: Musi
mesh_terms: D000293:Adolescent; D000328:Adult; D001786:Blood Glucose / Q000378:metabolism; D019852:Diacylglycerol Kinase / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D016328:NF-kappa B; D051193:Toll-Like Receptors; D019852:Diacylglycerol Kinase; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases