Identification of α-ionone, nootkatone, and their derivatives as TGR5 agonists
Identification of α-ionone, nootkatone, and their derivatives as TGR5 agonists
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α-紫罗兰酮、诺卡酮及其衍生物作为 TGR5 激动剂的鉴定
DOI：
10.1016/j.bbrc.2023.02.070
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发表时间：
2023
影响因子：
3.1
通讯作者：
Sato Ryuichiro
中科院分区：
文献类型：
--
作者：
Sasaki Takashi;Ikari Naho;Hashimoto Shuzo;Sato Ryuichiro
TGR5是一种G蛋白偶联受体，可被胆汁酸激活。棕色脂肪组织(BAT)中TGR5的激活通过增加产热相关基因的表达水平来增加能量消耗，如过氧化体增殖物激活的受体-γ共激活物1-α、解偶联蛋白1和II型碘甲状腺原氨酸脱碘酶。因此，TGR5是治疗肥胖及相关代谢紊乱的潜在药物靶点。在本研究中，我们利用荧光素酶报告系统鉴定了香气化合物α-紫罗兰酮和nootkatone及其衍生物为TGR5激动剂。这些化合物对法尼醇X受体的活性几乎没有影响，法尼醇X受体是一种由胆汁酸激活的核受体。与饲喂正常高脂饲料的小鼠相比，饲喂0.2%α-紫罗兰酮的高脂饲料小鼠BAT中产热相关基因的表达水平增加，体重增加受到抑制。这些发现表明，具有TGR5激动剂活性的芳香族化合物是很有前途的预防肥胖的化学物质。
TGR5 is a G-protein-coupled receptor that is activated by bile acids. The activation of TGR5 in brown adipose tissue (BAT) increases energy expenditure by increasing the expression level of thermogenesis-related genes, such as peroxisome proliferator-activated receptor-gamma coactivator 1-alpha, uncoupling protein 1, and type II iodothyronine deiodinase. Therefore, TGR5 is a potential drug target in treating obesity and associated metabolic disorders. In this study, we identified the aroma compounds α-ionone and nootkatone as well as their derivatives as TGR5 agonists by using the luciferase reporter assay system. These compounds had little effect on the activity of the farnesoid X receptor, a nuclear receptor activated by bile acids. Mice fed 0.2% α-ionone containing high-fat diet (HFD) increased the thermogenesis-related gene expression level in BAT and suppressed weight gain compared with mice fed a normal HFD. These findings indicate that aromatic compounds with TGR5 agonist activity are promising chemicals to prevent obesity.