Elaiophylin reduces body weight and lowers glucose levels in obese mice by activating AMPK.
Elaiophylin reduces body weight and lowers glucose levels in obese mice by activating AMPK.
复制标题
Elaiophylin 通过激活 AMPK 减轻肥胖小鼠的体重并降低血糖水平
DOI：
10.1038/s41419-021-04264-9
复制
发表时间：
2021-10-20
影响因子：
9
通讯作者：
Dang Y
中科院分区：
文献类型：
--
作者：
Bao R;Meng Y;Zhang H;Yang C;Li W;Zhang C;Zhang J;Sun R;Li Z;Jiang W;Zhang C;Zhang C;Yuan HX;Dang Y
肥胖是一种流行病，影响着全球13%的人口，并增加了许多慢性疾病的风险。然而，只有几种药物被许可用于治疗肥胖的药理干预。作为代谢的主要调节因子，AMPK的治疗潜力被广泛认可并积极用于代谢性疾病的治疗。我们发现elaiophylin （Ela）在一组癌细胞系以及原代肝细胞和脂肪细胞中迅速激活AMPK。同时，Ela抑制mTORC1复合物，与AMPK一起开启分解代谢并关闭合成代谢。体外和体内研究表明，Ela不直接激活AMPK，而是增加细胞AMP/ATP和ADP/ATP的比率，导致AMPK以lkb1依赖的方式磷酸化。Ela诱导AMPK活化引起多种代谢基因的改变，从而促进葡萄糖消耗和脂肪酸氧化。重要的是，Ela激活小鼠肝脏和脂肪组织中的AMPK。因此，在ob/ob和高脂肪饮食诱导的肥胖小鼠模型中，它都能降低体重和血糖水平，提高葡萄糖和胰岛素耐受性。我们的研究已经确定了一种新的AMPK激活剂作为治疗肥胖及其相关慢性疾病的候选药物。
Obesity is an epidemic affecting 13% of the global population and increasing the risk of many chronic diseases. However, only several drugs are licensed for pharmacological intervention for the treatment of obesity. As a master regulator of metabolism, the therapeutic potential of AMPK is widely recognized and aggressively pursued for the treatment of metabolic diseases. We found that elaiophylin (Ela) rapidly activates AMPK in a panel of cancer-cell lines, as well as primary hepatocytes and adipocytes. Meanwhile, Ela inhibits the mTORC1 complex, turning on catabolism and turning off anabolism together with AMPK. In vitro and in vivo studies showed that Ela does not activate AMPK directly, instead, it increases cellular AMP/ATP and ADP/ATP ratios, leading to AMPK phosphorylation in a LKB1-dependent manner. AMPK activation induced by Ela caused changes in diverse metabolic genes, thereby promoting glucose consumption and fatty acid oxidation. Importantly, Ela activates AMPK in mouse liver and adipose tissue. As a consequence, it reduces body weight and blood glucose levels and improves glucose and insulin tolerance in both ob/ob and high-fat diet-induced obese mouse models. Our study has identified a novel AMPK activator as a candidate drug for the treatment of obesity and its associated chronic diseases.
登录
查看更多内容
影响因子：
15.9
作者：
Kahn, BB;Flier, JS
通讯作者：
Flier, JS
影响因子：
--
作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
通讯作者：
Hardie DG
影响因子：
29
作者：
Gowans GJ;Hawley SA;Ross FA;Hardie DG
通讯作者：
Hardie DG
影响因子：
7.7
作者：
Hardie DG
通讯作者：
Hardie DG
影响因子：
7.7
作者：
Jorgensen, SB;Nielsen, JN;Wojtaszewski, JFP
通讯作者：
Wojtaszewski, JFP