title: Loss of function mutation in toll-like receptor-4 does not offer protection against obesity and insulin resistance induced by a diet high in trans fat in mice.
abstract: BACKGROUND
  Toll-like receptor-4 (TLR4) triggers inflammatory signaling in response to microbial lipoploysaccharide. It has been reported that loss of TLR4 protected against saturated fat-induced inflammation and insulin resistance. It is not known whether loss of TLR4 function offers protection against trans fat (TF) induced obesity, inflammation, and insulin resistance. We investigated whether mice with loss of function mutation in TLR4 were resistant to TF-induced pathologies such as obesity, inflammation, hyperglycemia, and hyperinsulinemia.
  
  
  METHODS
  C57BL/6j and C57BL/10 mice were cross bred to generate TLR4 mutant and wild type (WT). TLR4 mutant (n = 12) and WT (n = 12) mice were fed either low fat (LF) (13.5% fat energy) or high TF diets (60% fat energy) for 12 weeks. In vitro experiments were conducted on mouse macrophage cells (RAW 264.7 and J774A.1) to investigate whether elaidic (trans 18:1) or oleic acid (cis 18:1) would upregulate inflammatory markers.
  
  
  RESULTS
  TLR4 mutant mice were ~26.4% heavier than WT mice. In both genotypes, mice that received TF diet were significantly heavier than those mice that received LF diet (P < 0.01). TLR4 mutant mice compared to WT mice had significantly higher fasting blood glucose, serum insulin, insulin resistance, serum leptin, and serum cholesterol when they received TF diet (P < 0.05). No upregulation of iNOS or COX2 in response to either elaidic or oleic acid in macrophage cells was observed.
  
  
  CONCLUSIONS
  Loss of function mutation in TLR4 not only did not protect mice from TF-induced obesity, hyperglycemia, hyperinsulinemia, and hypercholesterolemia but also exacerbated the above pathologies suggesting that functional TLR4 is necessary in attenuating TF-induced deleterious effects. It is likely that TF induces pathologies through pathways independent of TLR4.
authors.affiliation: Division of Nutrition, School of Health Professions, College of Health and Human Sciences, Georgia State University, Atlanta, GA 30302, USA. vganji@gsu.edu.
authors.forename: Matam
authors.initials: M
authors.lastname: Vijay-Kumar
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Aitken
authors.forename: Frederic A
authors.initials: FA
authors.lastname: Carvalho
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Ziegler
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Gewirtz
authors.forename: Vijay
authors.initials: V
authors.lastname: Ganji