Toll-like receptor 2 deficiency improves insulin sensitivity and hepatic insulin signalling in the mouse

Abstract

Aims/hypothesis Substantial evidence suggests a link between elevated inflammation and development of insulin resistance. Toll-like receptor 2 (TLR2) recognises a large number of lipid-containing molecules and transduces inflammatory signalling in a variety of cell types, including insulin-responsive cells. Considering the contribution of the fatty acid composition in TLR2-depedent signalling, we hypothesised that the inflammatory signals transduced by TLR2 contribute to insulin resistance.Methods Mice deficient in TLR2 were used to investigate the in vivo roles of TLR2 in initiating and maintaining inflammation-associated insulin resistance and energy homeostasis.Results We first recapitulated the observation with elevated expression of TLR2 and inflammatory cytokines in white adipose tissue and liver of ob/ob mice. Aged or high-fat-fed TLR2-deficient mice were protected from obesity and adipocyte hypertrophy compared with wild-type mice. Moreover, mice lacking TLR2 exhibited improved glucose tolerance and insulin sensitivity regardless of feeding them regular chow or a high-fat diet. This is accompanied by reductions in expression of inflammatory cytokines and activation of extracellular signal-regulated kinase (ERK) in a liver-specific manner. The attenuated hepatic inflammatory cytokine expression and related signalling are correlated with increased insulin action specifically in the liver in TLR2-deficient mice, reflected by increased insulinstimulated protein kinase B (Akt) phosphorylation and IRS1 tyrosine phosphorylation and increased insulinsuppressed hepatocyte glucose production. Conclusions/interpretation The absence of TLR2 attenuates local inflammatory cytokine expression and related signalling and increases insulin action specifically in the liver. Thus, our work has identified TLR2 as a key mediator of hepatic inflammation-related signalling and insulin resistance.

Toll-like receptor 2 mediates high-fat diet-induced impairment of vasodilator actions of insulin

“…Tissue-specific knockout of TLR2 in the vasculature in our study opposes this pathophysiology. Lack of TLR was able to protect against HFD-induced obesity in some (24,38), but not all (8,48), previous studies. From these mixed results, it remains unclear whether TLRs play a role in HFD-induced body weight gain.…”

“…Phosphorylation of IRS-1 at Ser 24 impairs insulin-stimulated activation of PI 3-kinase and Akt (12,19). Treatment of endothelial cells with palmitate increased phosphorylation of IRS-1 at Ser 24 . This was opposed by siRNA knockdown of TLR2 (Fig.…”

Innate immunity in diabetes and diabetic nephropathy

“…Furthermore, the absence of TLR2 was shown to attenuate local inflammatory cytokine expression and enhance insulin action in the liver 54 . Although TLR2 is implicated in the inflammatory response in high-fat diet (HFD)-induced obesity in rodents and in human gene expression studies 55 , saturated and polyunsaturated fatty acids did not elicit proinflammatory effects in human adipose tissue and primary adipocyte culture 56 .…”

Toll-like receptor 4-induced endoplasmic reticulum stress contributes to impairment of vasodilator action of insulin

“…Elevated circulating fatty acids in human subjects with obesity and diabetes contribute to impaired vascular function, which is associated with metabolic and cardiovascular disorders (1,7,58). Obesity-induced inflammatory responses are mediated, in part, by Toll-like receptors (TLRs) that are activated by saturated fatty acids (SFA) (12,14,24,29,32,53). SFA-stimulated TLR4 (33) increases expression of proinflammatory cytokines, including TNF␣, IL-1␤, and IL-6, as well as adhesion molecules, including E-selectin and intercellular adhesion molecule (ICAM) (24,44,60).…”