title: Loss of toll-like receptor 3 function improves glucose tolerance and reduces liver steatosis in obese mice.
abstract: OBJECTIVE
  Emerging evidence suggests a link between innate immunity and development of type 2 diabetes mellitus (T2D); however, the molecular mechanisms linking them are not fully understood. Toll-like Receptor 3 (TLR3) is a pathogen pattern recognition receptor that recognizes the double-stranded RNA of microbial or mammalian origin and contributes to immune responses in the context of infections and chronic inflammation. The objective of this study was to determine whether TLR3 activity impacts insulin sensitivity and lipid metabolism.
  
  
  METHODS
  Wild type (WT) and TLR3 knock-out (TLR3(-/-)) mice were fed a high fat diet (HFD) and submitted to glucose tolerance tests (GTTs) over a period of 33 weeks. In another study, the same group of mice was treated with a neutralizing monoclonal antibody (mAb) against mouse TLR3.
  
  
  RESULTS
  TLR3(-/-) mice fed an HFD developed obesity, although they exhibited improved glucose tolerance and lipid profiles compared with WT obese mice. In addition, the increase in liver weight and lipid content normally observed in WT mice on an HFD was significantly ameliorated in TLR3(-/-) mice. These changes were accompanied by up-regulation of genes involved in cholesterol efflux such as PPARδ, LXRα, and LXRα-targeting genes and down-regulation of pro-inflammatory cytokine and chemokine genes in obese TLR3(-/-) mice. Furthermore, global gene expression profiling in liver demonstrated TLR3-specific changes in both lipid biosynthesis and innate immune response pathways.
  
  
  CONCLUSIONS
  TLR3 affects glucose and lipid metabolism as well as inflammatory mediators, and findings in this study reveal a new role for TLR3 in metabolic homeostasis. This suggests antagonizing TLR3 may be a beneficial therapeutic approach for the treatment of metabolic diseases.
authors.affiliation: Janssen Pharmaceutical Companies of Johnson & Johnson, USA. lwu4@its.jnj.com
authors.forename: Linda H
authors.initials: LH
authors.lastname: Wu
authors.forename: C Chris
authors.initials: CC
authors.lastname: Huang
authors.forename: Sree
authors.initials: S
authors.lastname: Adhikarakunnathu
authors.forename: Lani R
authors.initials: LR
authors.lastname: San Mateo
authors.forename: Karen E
authors.initials: KE
authors.lastname: Duffy
authors.forename: Patricia
authors.initials: P
authors.lastname: Rafferty
authors.forename: Peter
authors.initials: P
authors.lastname: Bugelski
authors.forename: Holly
authors.initials: H
authors.lastname: Raymond
authors.forename: Heather
authors.initials: H
authors.lastname: Deutsch
authors.forename: Kristen
authors.initials: K
authors.lastname: Picha
authors.forename: Christine K
authors.initials: CK
authors.lastname: Ward
authors.forename: Lena
authors.initials: L
authors.lastname: Alexoupolou
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: M Lamine
authors.initials: ML
authors.lastname: Mbow
authors.forename: Vedrana S
authors.initials: VS
authors.lastname: Susulic
mesh_terms: D000818:Animals; D005234:Fatty Liver / Q000503:physiopathology*; D020869:Gene Expression Profiling; D005951:Glucose Tolerance Test; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000503:physiopathology*; D060888:Real-Time Polymerase Chain Reaction; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000502:physiology*
chemical_list: C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3