TAK-242, a small-molecule inhibitor of Toll-like receptor 4 signalling, unveils similarities and differences in lipopolysaccharide- and lipidinduced inflammation and insulin resistance in muscle cells

Abstract

Emerging evidence suggests that TLR (Toll-like receptor) 4 and downstream pathways [MAPKs (mitogen-activated protein kinases) and NF-κB (nuclear factor κB)] play an important role in the pathogenesis of insulin resistance. LPS (lipopolysaccharide) and saturated NEFA (non-esterified fatty acids) activate TLR4, and plasma concentrations of these TLR4 ligands are elevated in obesity and Type 2 diabetes. Our goals were to define the role of TLR4 on the insulin resistance caused by LPS and saturated NEFA, and to dissect the independent contribution of LPS and NEFA to the activation of TLR4-driven pathways by employing TAK-242, a specific inhibitor of TLR4. LPS caused robust activation of the MAPK and NF-κB pathways in L6 myotubes, along with impaired insulin signalling and glucose transport. TAK-242 completely prevented the inflammatory response (MAPK and NF-κB activation) caused by LPS, and, in turn, improved LPS-induced insulin resistance. Similar to LPS, stearate strongly activated MAPKs, although stimulation of the NF-κB axis was modest. As seen with LPS, the inflammatory response caused by stearate was accompanied by impaired insulin action. TAK-242 also blunted stearate-induced inflammation; yet, the protective effect conferred by TAK-242 was partial and observed only on MAPKs. Consequently, the insulin resistance caused by stearate was only partially improved by TAK-242. In summary, TAK-242 provides complete and partial protection against LPS- and NEFA-induced inflammation and insulin resistance, respectively. Thus, LPS-induced insulin resistance depends entirely on TLR4, whereas NEFA works through TLR4-dependent and -independent mechanisms to impair insulin action.

Palmitate-induced inflammatory pathways in human adipose microvascular endothelial cells promote monocyte adhesion and impair insulin transcytosis

“…It has been proposed that fatty acids can act on TLRs, leading to activation of the NF-B transcription factor (41). TLR4 can be selectively inhibited by TAK242 (23), while cardamonin prevents IKK phosphorylation and the consequent NF-B activation (21). We verified that TAK242 and cardamonin act accordingly in HAMEC, as these inhibitors eliminated the induction of cytokines and adhesion molecules provoked by the canonical TLR4 agonist LPS (data not shown).…”

Innate immunity in diabetes and diabetic nephropathy

“…These DAMPs can induce insulin resistance and TLR4 and NLRP3 inflammasome-dependent IL1β production in adipose tissue, macrophages, and neutrophils in both mice and humans 80 . A small-molecule inhibitor of TLR4 signaling, TAK-242, provides complete protection against LPS-induced and non-esterified fatty acid-induced inflammation in muscle cells and partial protection against insulin resistance 81 . The identification of endogenous ligands and their inhibitors is required to facilitate the development of therapeutic agents to ameliorate inflammation, insulin resistance, and obesity.…”

Protective Effect of Ginsenosides Rg1 and Re on Lipopolysaccharide-Induced Sepsis by Competitive Binding to Toll-Like Receptor 4

“…Sprague Dawley rats were intravenously administered saline solution, 1 mg of Rg1/kg body weight (1 mg/kg Rg1), 1 mg/kg Re, or 1 mg/kg TAK-242, a novel TLR4 inhibitor (27). Fifteen minutes later, rats were challenged with 2.5 g/kg LPS.…”