Niwa Manabu, Numaguchi Yasushi, Ishii Masakazu, Kuwahata Tomomi, Kondo Megumi, Shibata Rei, Miyata Keishi, Oike Yuichi, Murohara Toyoaki
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Biochem Biophys Res Commun. 2015 Jan 30;457(1):12-8. doi: 10.1016/j.bbrc.2014.12.071. Epub 2014 Dec 19.
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.
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.
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.
脂肪组织肾素 - 血管紧张素系统的激活有助于肥胖和代谢综合征的发展。胰岛素调节氨肽酶（IRAP）已被确定为葡萄糖转运蛋白4（GLUT4）以及血管紧张素IV（AngIV）受体（AT4R）的关键调节因子。尽管血管紧张素II - 1型血管紧张素受体（AngII - AT1R）轴表现为食欲抑制和能量消耗的效应器，但AngIV - IRAP/AT4R轴对能量代谢的影响仍不清楚。目的是确定IRAP在小鼠能量代谢中的作用。
在脂肪细胞培养中，与野生型（C57Bl/6J，WT）小鼠相比，IRAP基因敲除（IRAP(-/-)）小鼠中纤溶酶原激活物抑制剂1（PAI - 1）的表达水平降低。8周龄的小鼠喂食高脂肪饮食（32%脂肪）。开始时，各组之间的体重、体脂含量和糖代谢参数相似。然而，尽管食物摄入量和身体活动相当，但与WT小鼠相比，IRAP(-/-)小鼠的体重增加变缓。在20周龄时，IRAP(-/-)小鼠的体重比WT小鼠低25%。葡萄糖和胰岛素耐量试验表明，高脂饮食后，IRAP(-/-)小鼠的葡萄糖处置和胰岛素的降血糖作用明显。间接测热法表明，IRAP(-/-)小鼠的全身耗氧率显著提高18%，伴有轻度体温升高。对IRAP(-/-)小鼠棕色脂肪组织（BAT）的分析显示，基础水平的解偶联蛋白 - 1（UCP - 1）水平升高，适应性产热未受损。
IRAP缺乏可能导致脂肪细胞中PAI - 1表达受抑制，BAT中UCP - 1介导的产热上调以及能量消耗增加，从而预防肥胖的发生，这些事实表明IRAP/AT4R阻断在饮食诱导的肥胖中具有治疗潜力。
