中科院上海分院在PNAS上报道减肥植物有效成分及机制

蝴蝶亚是一类生长在南非高温乾燥的喀拉哈利沙漠(Kalahari Deseret)地区的类似仙人掌的植物，当地土著在漫长的狩猎行动中吃这类植物以抑制食欲。有文献报道该植物中的一个化合物P57是其抑制食欲的主要活性成分，但其作用机制并不清楚。天然资源的有限及知识产权的争端使许多国际大公司放弃了对蝴蝶亚的开发。

研究团队通过大量化合物筛选发现一个提取自蝴蝶亚的化合物Gordonoside F，而不是原先报道的P57，可以特异性激活与代谢密切相关的g蛋白偶联受体GPR119。Gordonoside F的成功全合成使研究人员可以在动物体内考察其活性。Gordonoside F通过激活GPR119刺激胰高血糖素样肽-1(GLP-1)和胰岛素的分泌，并抑制小鼠食欲。

在GPR119敲除小鼠中，其药效消失。更有意思的是，蝴蝶亚的粗提物也是部分通过激活GPR119来抑制食欲的。这类新型GPR119激动剂的发现为抗肥胖药物的开发奠定良好基础。

论文的第一作者为来自同济大学的联合培养研究生张书永同学(负责生物学部分研究)和上海有机所的马玉勇同学(负责化学部分研究)。本研究工作得到新药创制重大专项、国家自然科学基金、973及上海市科委项目的支持。

原文摘要：

Molecular matchmaking between the popular weight-loss herb Hoodia gordonii and GPR119, a potential drug target for metabolic disorder

Shuyong Zhang, Yuyong Ma, Jing Li, Junjun Ma, Biao Yu and Xin Xie

African cactiform Hoodia gordonii (Asclepiadaceae) has been used for thousands of years by Xhomani Bushmen as an anorexant during hunting trips and has been proposed as a new agent for the management of body weight. However, its in vivo targets and molecular mechanisms remain elusive. GPR119, a G protein-coupled receptor highly expressed in pancreatic β cells and intestinal L cells, has been demonstrated to facilitate glucose-stimulated insulin secretion (GSIS) and represents a novel and attractive target for the therapy of metabolic disorders. Here, we disclose that Gordonoside F (a steroid glycoside isolated from H. gordonii), but not the widely known P57, activates specifically GPR119. Successful synthesis of Gordonoside F facilitates further characterization of this compound. Gordonoside F promotes GSIS both in vitro and in vivo and reduces food intake in mice. These effects are mediated by GPR119 because GPR119 knockout prevents the therapeutic effects of Gordonoside F. Interestingly, the appetite-suppressing effect of Hoodiaextract was also partially blocked by GPR119 knockout. Our results demonstrate for the first time, to our knowledge, that GPR119 is a direct target and one of the major mechanisms underlying the therapeutic effect of the popular “weight loss” herb H. gordonii. Given the long history of safe application of this herb in weight control, it is foreseeable that the novel scaffold of Gordonoside F provides a promising opportunity to develop new drugs in treating metabolic diseases.

作者：中科院上海分院