title: TRAIL receptor deletion in mice suppresses the inflammation of nutrient excess.
abstract: OBJECTIVE
  Low-grade chronic inflammation is a cardinal feature of the metabolic syndrome, yet its pathogenesis is not well defined. The purpose of this study was to examine the role of TRAIL receptor (TR) signaling in the pathogenesis of obesity-associated inflammation using mice with the genetic deletion of TR.
  
  
  METHODS
  TR knockout (TR(-/-)) mice and their littermate wild-type (WT) mice were fed a diet high in saturated fat, cholesterol and fructose (FFC) or chow. Metabolic phenotyping, liver injury, and liver and adipose tissue inflammation were assessed. Chemotaxis and activation of mouse bone marrow-derived macrophages (BMDMϕ) was measured.
  
  
  RESULTS
  Genetic deletion of TR completely repressed weight gain, adiposity and insulin resistance in FFC-fed mice. Moreover, TR(-/-) mice suppressed steatohepatitis, with essentially normal serum ALT, hepatocyte apoptosis and liver triglyceride accumulation. Gene array data implicated inhibition of macrophage-associated hepatic inflammation in the absence of the TR. In keeping with this, there was diminished accumulation and activation of inflammatory macrophages in liver and adipose tissue. TR(-/-) BMDMϕ manifest reduced chemotaxis and diminished activation of nuclear factor-κ B signaling upon activation by palmitate and lipopolysaccharide.
  
  
  CONCLUSIONS
  These data advance the concept that macrophage-associated hepatic and adipose tissue inflammation of nutrient excess requires TR signaling.
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States.
authors.forename: Leila
authors.initials: L
authors.lastname: Idrissova
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States. Electronic address: malhi.harmeet@mayo.edu.
authors.forename: Harmeet
authors.initials: H
authors.lastname: Malhi
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States.
authors.forename: Nathan W
authors.initials: NW
authors.lastname: Werneburg
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, United States.
authors.forename: Nathan K
authors.initials: NK
authors.lastname: LeBrasseur
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Bronk
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States.
authors.forename: Christian
authors.initials: C
authors.lastname: Fingas
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, United States.
authors.forename: Tamar
authors.initials: T
authors.lastname: Tchkonia
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, United States.
authors.forename: Tamar
authors.initials: T
authors.lastname: Pirtskhalava
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, United States.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: White
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, United States.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Stout
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States.
authors.forename: Petra
authors.initials: P
authors.lastname: Hirsova
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Krishnan
authors.affiliation: Department of Medicine III, University Hospital, Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Liedtke
authors.affiliation: Department of Medicine III, University Hospital, Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.affiliation: Penn State Hershey Cancer Institute, Hershey, PA 17033, United States.
authors.forename: Niklas
authors.initials: N
authors.lastname: Finnberg
authors.affiliation: Penn State Hershey Cancer Institute, Hershey, PA 17033, United States.
authors.forename: Wafik S
authors.initials: WS
authors.lastname: El-Deiry
authors.affiliation: Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, United States.
authors.forename: James L
authors.initials: JL
authors.lastname: Kirkland
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905, United States. Electronic address: gores.gregory@mayo.edu.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gores
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002633:Chemotaxis; D059305:Diet, High-Fat / Q000379:methods; D004195:Disease Models, Animal; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000150:complications / Q000378:metabolism / Q000473:pathology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand
keywords: Lipoapoptosis; Macrophage activation; Metainflammation; Non-alcoholic fatty liver disease