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

Diabetologia. 2011 Jan;54(1):168-79. doi: 10.1007/s00125-010-1931-5. Epub 2010 Oct 22.

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 insulin-stimulated protein kinase B (Akt) phosphorylation and IRS1 tyrosine phosphorylation and increased insulin-suppressed 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight / genetics
  • Body Weight / physiology
  • Cytokines / metabolism
  • Energy Metabolism / genetics
  • Energy Metabolism / physiology
  • Female
  • Glucose / metabolism
  • Insulin / metabolism*
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Toll-Like Receptor 2 / deficiency*
  • Toll-Like Receptor 2 / genetics

Substances

  • Cytokines
  • Insulin
  • Tlr2 protein, mouse
  • Toll-Like Receptor 2
  • Glucose