IRAP Deficiency Attenuates Diet-induced Obesity in Mice Through Increased Energy Expenditure.

  • Niwa M
  • Numaguchi Y
  • Ishii M
 et al. 
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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 METHODS AND 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 20 weeks 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 leads 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 suggest a therapeutic potential of IRAP/AT4R blockade in diet-induced obesity.

Author-supplied keywords

  • AT1R
  • AT2R
  • AT4R
  • Ang
  • BAT
  • Brown adipose tissue
  • Diet-induced obesity
  • IRAP
  • Insulin-regulated aminopeptidase
  • PAI-1
  • PGC
  • PPAR
  • RAS
  • UCP
  • UCP-1
  • WAT
  • WT
  • angiotensin
  • angiotensin II type 1 receptor
  • angiotensin II type 2 receptor
  • angiotensin IV receptor
  • brown adipose tissue
  • insulin-regulated aminopeptidase
  • peroxisome proliferator-activated receptor
  • peroxisome proliferator-activated receptor-$γ$ coa
  • plasminogen activator inhibitor type 1
  • renin–angiotensin system
  • uncoupling protein
  • white adipose tissue
  • wild type

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  • Manabu Niwa

  • Yasushi Numaguchi

  • Masakazu Ishii

  • Tomomi Kuwahata

  • Megumi Kondo

  • Rei Shibata

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