title: Tumor necrosis factor-α converting enzyme inactivation ameliorates high-fat diet-induced insulin resistance and altered energy homeostasis.
abstract: BACKGROUND
  Tumor necrosis factor (TNF)-α, which is released as a soluble form by ectodomain shedding of TNF-α converting enzyme (Tace), is known to play a pivotal role in obesity-induced insulin resistance. The role of Tace in obesity-induced metabolic disorders was to be clarified in this study.
  
  
  RESULTS
  Transgenic mice with temporal systemic Tace deletion (TaceMx1) and their non-transgenic littermates (CON) were fed a standard diet or a high-fat diet (HFD) from 6 weeks of age. The increased body, liver and epididymal adipose tissue (EAT) weights, systolic blood pressure, and fasting glucose and lipid levels and decreased serum adiponectin level 12 weeks after starting a HFD were suppressed by Tace inactivation. A HFD/TaceMx1 showed ameliorated glucose tolerance and insulin sensitivity compared with HFD/CON. Indirect calorimetry showed that energy expenditure and oxidation of both fat and carbohydrate were higher in HFD/TaceMx1 than HFD/CON. Marked hepatosteatosis, increased triglyceride content and TNF-α expression in liver, and increased adipocyte size, macrophage infiltration and TNF-α and monocyte chemoattractant protein-1 expression in EAT induced by a HFD were attenuated in HFD/TaceMx1.
  
  
  CONCLUSIONS
  Inactivation of Tace suppressed HFD-induced obesity, insulin resistance, hepatosteatosis and adipose tissue remodeling in association with increased energy expenditure, suggesting an important role of Tace in the development of obesity-induced metabolic disorders.
authors.affiliation: Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Kaneko
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Anzai
authors.forename: Keisuke
authors.initials: K
authors.lastname: Horiuchi
authors.forename: Kokichi
authors.initials: K
authors.lastname: Morimoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Anzai
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Nagai
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Sugano
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Maekawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Itoh
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Okada
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogawa
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
mesh_terms: D051722:ADAM Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000072198:ADAM17 Protein; D000273:Adipose Tissue; D000818:Animals; D004041:Dietary Fats / Q000494:pharmacology*; D004734:Energy Metabolism / Q000235:genetics*; D005234:Fatty Liver / Q000209:etiology; D017353:Gene Deletion; D006706:Homeostasis / Q000235:genetics*; D007333:Insulin Resistance; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse