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In contrast to this suppressive effect on IRS-1, lipid infusion had no significant effect on phosphorylation of Akt (Fig. (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 (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 (NFB and MAPK) in lean individuals. The activation of this pathway by NEFA may be involved in the pathogenesis of insulin resistance in humans. Keywords:Acylcarnitine, Ceramide, Diacylglycerol, Ibodutant (MEN 15596) Inflammation, Insulin resistance == Introduction == Over the past three decades a large body of evidence has implicated NEFA in the pathogenesis of skeletal muscle insulin resistance. For example, most individuals with obesity and type 2 diabetes have elevated plasma NEFA levels, which correlate with the severity of insulin resistance [1]. In insulin-resistant individuals, pharmacological reduction of plasma NEFA concentration with anti-lipolytic drugs improves insulin sensitivity [2]. Accordingly, acute experimental elevation in plasma NEFA levels (by systemic lipid infusion) rapidly induces skeletal muscle insulin resistance in lean healthy individuals [3,4]. Different theories have been proposed to explain how excess NEFAs cause insulin resistance in muscle. Studies in cultured cells and animals have shown that toxic metabolites of NEFAs and triacylglycerols, such as ceramides and diacylglycerols (DAGs), interfere with the insulin signalling pathway (i.e. lipotoxicity). An alternative theory proposes that NEFAs impair Ibodutant (MEN 15596) glucose metabolism by stimulating cell-surface receptors of the Toll-like receptor (TLR) family (TLR2 and TLR4) [5,6]. Common to both models (lipotoxicity and TLRs) is the stimulation of downstream pro-inflammatory signalling pathways, including the inhibitor of kappa B (IB) kinase (IKK)-nuclear factor B (NFB) and the mitogen-activated kinase (MAPK) axes. The activation of IKK and the MAPKs (extracellular signal-regulated kinase [ERK], c-Jun N-terminal kinase [JNK] and p38) impairs insulin signal transduction [7]. These inflammatory pathways also increase the transcription of genes whose products (i.e. TNF- and IL-6) are implicated in insulin resistance [7]. Notably, there is some evidence suggesting that TLR4 mediates NEFA-induced ceramide biosynthesis, raising the possibility that both proposed mechanisms of insulin resistance (intracellular lipids and TLR-mediated) are inextricably linked [8]. Inflammatory mediators in muscle, such as TLR4 [9], ERK [10], p38 [11], JNK [12] and NFB [9], are increased in obesity and type 2 diabetes. However it is unclear whether the upregulation of these inflammatory mediators is a direct result of elevated plasma NEFA levels in humans in vivo. In addition, some studies in lean healthy humans have shown that the insulin resistance caused by acute lipid infusion occurs in association with increased muscle content of ceramides and DAGs [4,13,14], whereas other studies have not found changes in muscle lipid content [1517]. Similarly, some [1820] but not all [13,15] studies have demonstrated impaired proximal insulin signalling following lipid infusion in humans. The discrepant Ibodutant (MEN 15596) findings are likely a result of the large variation in the lipid infusion protocols, most of them short ( 6 h) and some involving high lipid infusion rates and/or co-administration of heparin [3], which creates supraphysiological plasma NEFA levels by activating endothelial lipoprotein lipase. The aim of the present study was to test the hypothesis that a prolonged (48 h), mild increase in plasma NEFA will induce an inflammatory response in muscle of lean healthy individuals. We focused our analysis on TLR expression and TLR-driven pathways (NFB and MAPK), considering the substantial body of evidence generated in recent years about their potential role in the pathogenesis of insulin resistance [8,9,2123]. In addition, we tested whether the low-dose lipid infusion and its potential effect on inflammatory TNF pathways led to impairments in the phosphorylation of insulin signalling intermediaries. == Methods == == Participants == Twelve healthy, lean (BMI < 26 kg/m2), non-smoking, normal-glucose-tolerant, community-dwelling individuals (five men/seven women), without a family history of diabetes mellitus (first-degree relatives), were studied. Participants ranged from 18 to 60 years of age. Each participant underwent a physical.