Evodiamine inhibits insulin-stimulated mTOR-S6K activation and IRS1 serine phosphorylation in adipocytes and improves glucose tolerance in obese/diabetic mice.
Evodiamine inhibits insulin-stimulated mTOR-S6K activation and IRS1 serine phosphorylation in adipocytes and improves glucose tolerance in obese/diabetic mice.
复制标题
DOI：
10.1371/journal.pone.0083264
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Yamashita H
中科院分区：
文献类型：
--
作者：
Wang T;Kusudo T;Takeuchi T;Yamashita Y;Kontani Y;Okamatsu Y;Saito M;Mori N;Yamashita H
吴茱萸碱是一种从吴茱萸树（芸香科）未成熟干燥果实中提取的生物碱，可减少肥胖/糖尿病小鼠的肥胖和胰岛素抵抗；然而，吴茱萸碱对胰岛素抵抗的作用机制尚不清楚。本研究使用肥胖/糖尿病 KK-Ay 小鼠和体外脂肪细胞培养物研究了吴茱萸碱对与胰岛素抵抗相关的信号转导的影响。在用吴茱萸碱治疗的 KK-Ay 小鼠中，白色脂肪组织 (WAT) 中的哺乳动物雷帕霉素靶点 (mTOR) 和核糖体 S6 蛋白激酶 (S6K) 信号显着减少，葡萄糖耐量得到改善。此外，在它们的 WAT 中检测到胰岛素受体底物 1 (IRS1) 丝氨酸磷酸化（胰岛素抵抗的指标）的减少，表明从 S6K 到 IRS1 的负反馈环受到抑制。除了刺激 IRS1 和 Akt 丝氨酸磷酸化外，胰岛素刺激的 mTOR 和 S6K 在 3T3-L1 脂肪细胞中的磷酸化也具有时间依赖性，而吴茱萸碱除了对 mTOR 磷酸化有抑制作用外，不影响其磷酸化。此外，吴茱萸碱抑制胰岛素刺激的 mTOR 和 S6K 磷酸化，导致脂肪细胞中 IRS1 丝氨酸磷酸化下调。吴茱萸碱还能刺激 AMP 激活蛋白激酶 (AMPK) 的磷酸化，AMPK 是能量代谢的重要调节因子，可能导致脂肪细胞中 mTOR 信号传导下调。在用罗格列酮处理的脂肪细胞中也发现了对 AMPK、mTOR 和 IRS1 磷酸化的类似作用。这些结果表明吴茱萸碱至少部分通过抑制脂肪细胞中的 mTOR-S6K 信号传导和 IRS1 丝氨酸磷酸化来改善葡萄糖耐量并防止与肥胖/糖尿病状态相关的胰岛素抵抗的进展。
Evodiamine, an alkaloid extracted from the dried unripe fruit of the tree Evodia rutaecarpa Bentham (Rutaceae), reduces obesity and insulin resistance in obese/diabetic mice; however, the mechanism underlying the effect of evodiamine on insulin resistance is unknown. This study investigated the effect of evodiamine on signal transduction relating to insulin resistance using obese/diabetic KK-Ay mice and an in vitro adipocyte culture. There is a significant decrease in the mammalian target of rapamycin (mTOR) and ribosomal S6 protein kinase (S6K) signaling in white adipose tissue (WAT) in KK-Ay mice treated with evodiamine, in which glucose tolerance is improved. In addition, reduction of insulin receptor substrate 1 (IRS1) serine phosphorylation, an indicator of insulin resistance, was detected in their WAT, suggesting suppression of the negative feedback loop from S6K to IRS1. As well as the stimulation of IRS1 and Akt serine phosphorylation, insulin-stimulated phosphorylation of mTOR and S6K is time-dependent in 3T3-L1 adipocytes, whereas evodiamine does not affect their phosphorylation except for an inhibitory effect on mTOR phosphorylation. Moreover, evodiamine inhibits the insulin-stimulated phosphorylation of mTOR and S6K, leading to down-regulation of IRS1 serine phosphorylation in the adipocytes. Evodiamine also stimulates phosphorylation of AMP-activated protein kinase (AMPK), an important regulator of energy metabolism, which may cause down-regulation of mTOR signaling in adipocytes. A similar effect on AMPK, mTOR and IRS1 phosphorylation was found in adipocytes treated with rosiglitazone. These results suggest evodiamine improves glucose tolerance and prevents the progress of insulin resistance associated with obese/diabetic states, at least in part, through inhibition of mTOR-S6K signaling and IRS1 serine phosphorylation in adipocytes.
登录
查看更多内容
影响因子：
7.7
作者：
Saito M;Okamatsu-Ogura Y;Matsushita M;Watanabe K;Yoneshiro T;Nio-Kobayashi J;Iwanaga T;Miyagawa M;Kameya T;Nakada K;Kawai Y;Tsujisaki M
通讯作者：
Tsujisaki M
影响因子：
64.8
作者：
Cunningham, John T.;Rodgers, Joseph T.;Puigserver, Pere
通讯作者：
Puigserver, Pere
影响因子：
4.9
作者：
Bak, E. J.;Park, H. G.;Cha, J-H
通讯作者：
Cha, J-H
影响因子：
4
作者：
Heo, Sook-Kyoung;Yun, Hyun-Jeong;Park, Sun-Dong
通讯作者：
Park, Sun-Dong
影响因子：
2.7
作者：
Kobayashi, Y;Nakano, Y;Kamiya, T
通讯作者：
Kamiya, T