Ohki Kohji, Wakui Hiromichi, Azushima Kengo, Uneda Kazushi, Haku Sona, Kobayashi Ryu, Haruhara Kotaro, Kinguchi Sho, Matsuda Miyuki, Ohsawa Masato, Maeda Akinobu, Minegishi Shintaro, Ishigami Tomoaki, Toya Yoshiyuki, Yamashita Akio, Umemura Satoshi, Tamura Kouichi
Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan.
Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.
Int J Mol Sci. 2017 Mar 21;18(3):676. doi: 10.3390/ijms18030676.
Activation of tissue renin-angiotensin system (RAS), mainly mediated by an angiotensin II (Ang II) type 1 receptor (AT1R), plays an important role in the development of obesity-related metabolic disorders. We have shown that AT1R-associated protein (ATRAP), a specific binding protein of AT1R, functions as an endogenous inhibitor to prevent excessive activation of tissue RAS. In the present study, we newly generated ATRAP/-floxed (ATRAP) mice and adipose tissue-specific ATRAP downregulated (ATRAP) mice by the Cre/loxP system using . Using these mice, we examined the functional role of adipose ATRAP in the pathogenesis of obesity-related metabolic disorders. Compared with ATRAP mice, ATRAP mice exhibited a decreased ATRAP expression in visceral white adipose tissue (WAT) and brown adipose tissue (BAT) by approximately 30% and 85%, respectively. When mice were fed a high-fat diet, ATRAP mice showed decreased endogenous ATRAP expression in WAT that was equivalent to ATRAP mice, and there was no difference in the exacerbation of dietary obesity and glucose and lipid metabolism. These results indicate that ATRAP in BAT does not influence the pathogenesis of dietary obesity or metabolic disorders. Future studies that modulate ATRAP in WAT are necessary to assess its in vivo functions in the development of obesity-related metabolic disorders.
组织肾素-血管紧张素系统（RAS）的激活主要由1型血管紧张素II（Ang II）受体（AT1R）介导，在肥胖相关代谢紊乱的发生发展中起重要作用。我们已经表明，AT1R相关蛋白（ATRAP）作为AT1R的特异性结合蛋白，可作为内源性抑制剂来防止组织RAS的过度激活。在本研究中，我们通过使用Cre/loxP系统新生成了ATRAP基因条件性敲除（ATRAP）小鼠和脂肪组织特异性ATRAP下调（ATRAP）小鼠。利用这些小鼠，我们研究了脂肪组织中ATRAP在肥胖相关代谢紊乱发病机制中的功能作用。与ATRAP小鼠相比，ATRAP小鼠在内脏白色脂肪组织（WAT）和棕色脂肪组织（BAT）中的ATRAP表达分别降低了约30%和85%。当给小鼠喂食高脂饮食时，ATRAP小鼠WAT中的内源性ATRAP表达降低程度与ATRAP小鼠相当，在饮食性肥胖及葡萄糖和脂质代谢的加重方面没有差异。这些结果表明，BAT中的ATRAP不影响饮食性肥胖或代谢紊乱的发病机制。未来有必要开展调节WAT中ATRAP的研究，以评估其在肥胖相关代谢紊乱发生发展中的体内功能。
