title: IRAP deficiency attenuates diet-induced obesity in mice through increased energy expenditure.
abstract: Activation of the adipose renin-angiotensin system contributes to the development of obesity and metabolic syndrome. Insulin-regulated aminopeptidase (IRAP) has been identified a key regulator of GLUT4 transporter as well as angiotensin IV (AngIV) receptor (AT4R). Although AngII-AT1R axis appears as anorexigenic and as an effector of energy expenditure, the impact of AngIV-IRAP/AT4R axis on energy metabolism remains unknown. The aim was to determine the role of IRAP in energy metabolism in mice.
  
  
  RESULTS
  In adipocyte culture, plasminogen activator inhibitor type 1 (PAI-1) expression levels were diminished in IRAP knockout (IRAP(-/-)) if compared with those of wild-type (C57Bl/6J, WT) mice. Mice were fed high-fat diet (32% fat) at age of 8 weeks. At the entry, body weight, body fat content, and parameters of saccharometabolism were similar between groups. However, IRAP(-/-) mice exhibited blunted body weight gain compared to that of WT mice, despite comparable food intake and physical activity. At 20weeks of age, IRAP(-/-) mice had 25% lower body weight than WT mice. Glucose and insulin tolerance tests revealed that the glucose disposal and the hypoglycemic effect of insulin were pronounced in IRAP(-/-) mice after a high fat diet. Indirect calorimetry demonstrated that whole-body oxygen consumption rates were significantly higher in IRAP(-/-) mice by 18% with mild hyperthermia. Analysis of brown adipose tissue (BAT) in IRAP(-/-) showed increased levels of uncoupling protein-1 (UCP-1) at basal level and adaptive thermogenesis was not impaired.
  
  
  CONCLUSIONS
  IRAP deficiency may lead to suppression of PAI-1 expression in adipocytes and upregulation of UCP-1-mediated thermogenesis in BAT and increased energy expenditure to prevent the development of obesity, and these facts suggest a therapeutic potential of IRAP/AT4R blockade in diet-induced obesity.
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Niwa
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: numa2@med.nagoya-u.ac.jp.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Numaguchi
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ishii
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kuwahata
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Kondo
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Rei
authors.initials: R
authors.lastname: Shibata
authors.affiliation: Department of Molecular Genetics, Kumamoto University Graduate School of Medicine, Kumamoto, Japan.
authors.forename: Keishi
authors.initials: K
authors.lastname: Miyata
authors.affiliation: Department of Molecular Genetics, Kumamoto University Graduate School of Medicine, Kumamoto, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oike
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D003080:Cold Temperature; D010122:Cystinyl Aminopeptidase / Q000172:deficiency* / Q000378:metabolism; D004032:Diet; D004734:Energy Metabolism; D007473:Ion Channels; D066292:Lipid Droplets / Q000378:metabolism; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins; D009043:Motor Activity; D009765:Obesity / Q000378:metabolism* / Q000517:prevention & control*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D000071256:Uncoupling Protein 1
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D017395:Plasminogen Activator Inhibitor 1; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase
keywords: Brown adipose tissue; Diet-induced obesity; Insulin-regulated aminopeptidase; UCP-1