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

doi:10.1007/s00125-013-3111-x

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 journal › Article › peer-review

31 Scopus citations

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 language	English (US)
Pages (from-to)	582-591
Number of pages	10
Journal	Diabetologia
Volume	57
Issue number	3
DOIs	https://doi.org/10.1007/s00125-013-3111-x
State	Published - Mar 2014

Keywords

Acylcarnitine
Ceramide
Diacylglycerol
Inflammation
Insulin resistance

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism

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10.1007/s00125-013-3111-x

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title = "A sustained increase in plasma NEFA upregulates the Toll-like receptor network in human muscle",

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",

keywords = "Acylcarnitine, Ceramide, Diacylglycerol, Inflammation, Insulin resistance",

author = "Hussey, {Sophie E.} and Helen Lum and Andrea Alvarez and Yolanda Cipriani and Jes{\'u}s Gardu{\~n}o-Garcia and Luis Anaya and John Dube and Nicolas Musi",

note = "Funding Information: Funding This work was supported by grants from the National Institutes of Health (NIH) (RO1-DK80157 and RO1-DK089229) and the American Diabetes Association to NM. This grant was supported by a University of Texas Health Science Center at San Antonio Clinical and Translational Science Award (TR000149) and an NIH National Service Research Award, Parent F32 (1F32DK095565-01A1) to SH. The research was supported in part by the Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina (MUSC) (P30 CA138313) and the Lipidomics Core in the South Carolina Lipidomics and Pathobiology COBRE, Department Biochemistry, MUSC (P20 RR017677). This project also was supported by the National Center for Research Resources and the Office of the Director of the NIH (C06 RR018823) to MUSC.",

year = "2014",

month = mar,

doi = "10.1007/s00125-013-3111-x",

language = "English (US)",

volume = "57",

pages = "582--591",

journal = "Diabetologia",

issn = "0012-186X",

publisher = "Springer Verlag",

number = "3",

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TY - JOUR

T1 - A sustained increase in plasma NEFA upregulates the Toll-like receptor network in human muscle

AU - Hussey, Sophie E.

AU - Lum, Helen

AU - Alvarez, Andrea

AU - Cipriani, Yolanda

AU - Garduño-Garcia, Jesús

AU - Anaya, Luis

AU - Dube, John

AU - Musi, Nicolas

N1 - Funding Information: Funding This work was supported by grants from the National Institutes of Health (NIH) (RO1-DK80157 and RO1-DK089229) and the American Diabetes Association to NM. This grant was supported by a University of Texas Health Science Center at San Antonio Clinical and Translational Science Award (TR000149) and an NIH National Service Research Award, Parent F32 (1F32DK095565-01A1) to SH. The research was supported in part by the Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina (MUSC) (P30 CA138313) and the Lipidomics Core in the South Carolina Lipidomics and Pathobiology COBRE, Department Biochemistry, MUSC (P20 RR017677). This project also was supported by the National Center for Research Resources and the Office of the Director of the NIH (C06 RR018823) to MUSC.

PY - 2014/3

Y1 - 2014/3

N2 - 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

AB - 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

KW - Acylcarnitine

KW - Ceramide

KW - Diacylglycerol

KW - Inflammation

KW - Insulin resistance

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JO - Diabetologia

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

Abstract

Keywords

ASJC Scopus subject areas

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