A sustained increase in plasma NEFA upregulates the Toll-like receptor network in human muscle

Sophie E. Hussey, Helen Lum, Andrea Alvarez, Yolanda Cipriani, Jesús Garduño-Garcia, Luis Anaya, John Dube, Nicolas Musi

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Aims/hypothesis: 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/interpretation: 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. Trial registration ClinicalTrials.gov NCT01740817

Original languageEnglish (US)
Pages (from-to)582-591
Number of pages10
JournalDiabetologia
Volume57
Issue number3
DOIs
StatePublished - Mar 2014

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Toll-Like Receptors
Nonesterified Fatty Acids
Up-Regulation
Muscles
Insulin
Insulin Resistance
Phosphorylation
Lipids
Tyrosine
Glucose Clamp Technique
Ceramides
Diglycerides
Mitogen-Activated Protein Kinase Kinases
Extracellular Signal-Regulated MAP Kinases
Quadriceps Muscle
Mitogens
Type 2 Diabetes Mellitus
Phosphotransferases
Obesity
Inflammation

Keywords

  • Acylcarnitine
  • Ceramide
  • Diacylglycerol
  • Inflammation
  • Insulin resistance

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Hussey, S. E., Lum, H., Alvarez, A., Cipriani, Y., Garduño-Garcia, J., Anaya, L., ... Musi, N. (2014). A sustained increase in plasma NEFA upregulates the Toll-like receptor network in human muscle. Diabetologia, 57(3), 582-591. https://doi.org/10.1007/s00125-013-3111-x

A sustained increase in plasma NEFA upregulates the Toll-like receptor network in human muscle. / Hussey, Sophie E.; Lum, Helen; Alvarez, Andrea; Cipriani, Yolanda; Garduño-Garcia, Jesús; Anaya, Luis; Dube, John; Musi, Nicolas.

In: Diabetologia, Vol. 57, No. 3, 03.2014, p. 582-591.

Research output: Contribution to journalArticle

Hussey, SE, Lum, H, Alvarez, A, Cipriani, Y, Garduño-Garcia, J, Anaya, L, Dube, J & Musi, N 2014, 'A sustained increase in plasma NEFA upregulates the Toll-like receptor network in human muscle', Diabetologia, vol. 57, no. 3, pp. 582-591. https://doi.org/10.1007/s00125-013-3111-x
Hussey SE, Lum H, Alvarez A, Cipriani Y, Garduño-Garcia J, Anaya L et al. A sustained increase in plasma NEFA upregulates the Toll-like receptor network in human muscle. Diabetologia. 2014 Mar;57(3):582-591. https://doi.org/10.1007/s00125-013-3111-x
Hussey, Sophie E. ; Lum, Helen ; Alvarez, Andrea ; Cipriani, Yolanda ; Garduño-Garcia, Jesús ; Anaya, Luis ; Dube, John ; Musi, Nicolas. / A sustained increase in plasma NEFA upregulates the Toll-like receptor network in human muscle. In: Diabetologia. 2014 ; Vol. 57, No. 3. pp. 582-591.
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AU - Dube, John

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