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 nuclear factor of light polypeptide gene enhancer in B cells inhibitor α (p = 0.09). The muscle content of most diacyglycerol, 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.

Interorgan Metabolic Crosstalk in Human Insulin Resistance

“…During subsequent intravenous insulin stimulation, inhibitory serine-1101 phosphorylation of the insulin receptor substrate-1 (pIRS1-Ser1101) was higher, while phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB, Akt) phosphorylation were lower and associated with peripheral insulin resistance (FIGURE 3). Prolonged lipid infusion for 48 -90 h confirmed impaired insulin signaling (231) and stimulated inflammatory pathways, but did not seem to affect DAG, ceramides, or acylcarnitines (179,195). This might be due to the transient nature of the accumulation of lipid metabolites in muscle during lipid infusions (380).…”

Silica nanoparticles trigger hepatic lipid-metabolism disorder in vivo and in vitro

“…the liver. 38 Therefore, further studies on reducing the side effects of nanomaterial-based products will be of value in this regard. Further studies are suggested to perform reverse verification of TLR5 gene functions, followed by confirming the downstream-signaling pathway with regard to SiNP-induced hyperlipemia and hepatic steatosis.…”

Lipid-induced insulin resistance does not impair insulin access to skeletal muscle

“…Potential methods for the contribution of fat to endothelial dysfunction and insulin resistance include inflammation, as some studies demonstrate that infused lipid upregulates Tolllike receptors (22,23), although other studies do not support the involvement of inflammation (20) but cite a metabolic feedback mechanism, as proposed by Randle (34). Lipids have previously been shown to induce insulin resistance by inhibiting glucose transport (37) and reducing nonoxidative glucose disposal (33).…”