Abstract 11154: Insulin-Regulated Aminopeptidase Deficiency Attenuates Diet-Induced Obesity in Mice Through Increased Energy Expenditure
Activation of the adipose renin-angiotensin system contributes to the development of obesity and metabolic syndrome. Insulin-regulated aminopeptidase (IRAP) has been identified as a key regulator of GLUT4 transporter as well as angiotensin IV (AngIV) receptor (AT4R). Although the AngII-AT1R axis appears as anorexigenic and as an effector of energy expenditure, the impact of the AngIV-AT4R axis on energy metabolism remains unknown.
Methods and Results IRAP knockout (IRAP-/-) and wild-type (C57Bl/6J, WT) mice were fed high-fat diet (32% fat) at age of 8 weeks (n=20 to 25). At the entry, body weight, body fat content, and parameters of saccharometabolism were similar between WT and IRAP-/- mice. However, beginning at 13 weeks of age, IRAP-/- mice exhibited blunted body weight gain compared to that of WT mice, despite comparable food intake and locomotor activity. At 20 weeks of age, IRAP-/- mice had 25±1.8% lower body weight than WT mice (mean±SD). This was confirmed by abdominal CT scan showing lower body fat content (11.4±1.3% vs. 30.7±7.8% for WT, P=0.0078). The mean adipocyte area in epididymal fat was smaller in IRAP-/- mice compared to WT mice (2557±159 vs. 4115±330µm2, P=0.012). Glucose tolerance test and insulin tolerance test revealed that the glucose disposal and the hypoglycemic effect of insulin were deteriorated in each group as parallel as body weight was increased. However, the degrees were similar between the two groups during an observation period. Indirect calorimetry demonstrated that whole-body oxygen consumption was significantly higher in IRAP-/- mice by 18±0.3% (P=0.026) with mild hyperthermia (0.42±0.05°C, P=0.043). Analysis of brown adipose tissues (BAT) in IRAP-/- mice showed increased levels of uncoupling protein 1 (UCP1) at basal level and in response to cold exposure (3.0- and 2.8-fold vs. WT, respectively. P<0.01 in each). In IRAP-/- mice, the basal metabolism of BAT was increased and adaptive thermogenesis was not impaired.
Conclusions IRAP deficiency leads to upregulation of UCP-1-mediated thermogenesis in BAT and increased energy expenditure to prevent the development of obesity without affecting food intake and behavior. These results suggest a therapeutic potential of IRAP/AT4R blockade in diet-induced obesity.
- © 2011 by American Heart Association, Inc.