ACE2 exerts anti-obesity effect via stimulating brown adipose tissue and induction of browning in white adipose tissue
ACE2 exerts anti-obesity effect via stimulating brown adipose tissue and induction of browning in white adipose tissue
复制标题
DOI：
10.1152/ajpendo.00311.2019
复制
发表时间：
2019-12-01
影响因子：
5.1
通讯作者：
Hosoi, Hajime
中科院分区：
文献类型：
--
作者：
Kawabe, Yasuhiro;Mori, Jun;Hosoi, Hajime
血管紧张素II(Ang II)-血管紧张素II 1型受体(AT(1)R)轴在肥胖的病理生理学中起着关键作用。血管紧张素转换酶2(ACE2)通过将Ang II转化为血管紧张素1-7(Ang 1-7)来对抗Ang II/AT1R轴，Ang 1-7具有抗肥胖作用。在这项研究中，我们假设ACE2通过增加血管紧张素转换酶1-7的水平而发挥强大的减肥作用。我们将重组人血管紧张素转换酶2(Rh ACE2)注射到腹膜腔内。2.0mg.kg(-1).day(-1)连续28天灌胃给高脂饮食(HFD)诱导的肥胖小鼠。重组人血管紧张素转换酶2治疗可降低体重，改善糖代谢。更重要的是。重组人血管紧张素转换酶2增加高脂饲料喂养的小鼠的耗氧量并上调产热能力。在rhACE2治疗组，棕色脂肪组织(BAT)质量增加，胰岛素信号转导信号改善，解偶联蛋白-1(UCP-1)和含有16的PRD1-BF1-RIZ1同源结构域的蛋白水平增加。重要的是，皮下白色脂肪组织(SWAT)质量减少，伴随着褐变，这是由UCP-1表达增加建立的。褐变是组蛋白脱乙酰酶3下调导致H3K27乙酰化增加，GCN5和P300/CBP相关因子上调导致H3K9乙酰化增加的结果。这些结果提示，重组人血管紧张素转换酶2可能通过刺激BAT和诱导SWAT褐变而发挥抗肥胖作用。血管紧张素转换酶2和血管紧张素转换酶1-7轴是预防肥胖发展的一种潜在的治疗方法。
The angiotensin II (ANG II)-ANG II type 1 receptor (AT(1)R) axis is a key player in the pathophysiology of obesity. Angiotensin-converting enzyme 2 (ACE2) counteracts the ANG II/AT 1 R axis via converting ANG II to angiotensin 1-7 (Ang 1-7), which is known to have an anti-obesity effect. In this study, we hypothesized that ACE2 exerts a strong anti-obesity effect by increasing Ang 1-7 levels. We injected intraperitoneally recombinant human ACE2 (rhACE2. 2.0 mg.kg(-1).day(-1)) for 28 days to high-fat diet (HFD)induced obesity mice. rhACE2 treatment decreased body weight and improved glucose metabolism. Furthermore. rhACE2 increased oxygen consumption and upregulated thermogenesis in HFD-fed mice. In the rhACE2 treatment group, brown adipose tissue (BAT) mass increased, accompanied with ameliorated insulin signaling and increased protein levels of uncoupling protein-1 (UCP-1) and PRD1-BF1-RIZ1 homologous domain containing 16. Importantly, subcutaneous white adipose tissue (sWAT) mass decreased, concomitant with browning, which was established by the increase of UCP-1 expression. The browning is the result of increased H3K27 acetylation via the downregulation of histone deacetylase 3 and increased H3K9 acetylation via upregulation of GCN5 and P300/CBP-associated factor. These results suggest that rhACE2 exerts anti-obesity effects by stimulating BAT and inducing browning in sWAT. ACE2 and the Ang 1-7 axis represent a potential therapeutic approach to prevent the development of obesity.