A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents
A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents
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DOI：
10.1038/nm.3761
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发表时间：
2015-01-01
期刊：
影响因子：
82.9
通讯作者：
Tschop, Matthias H.
中科院分区：
文献类型：
--
作者：
Finan, Brian;Yang, Bin;Tschop, Matthias H.
我们报道了一种新的单体多肽的发现，它通过作为三种关键的代谢相关多肽受体的激动剂，在肥胖的啮齿动物模型中减轻体重和糖尿病并发症：胰升糖素样肽-1(GLP-1)、葡萄糖依赖的胰岛素样多肽(GIP)和胰升糖素受体。这种三重激动剂在每个受体上表现出超生理学效力和同等排列的成分活性，所有这些都没有与其他相关受体发生交叉反应。在相关啮齿动物模型中，这种平衡的单分子三激动剂在减轻体重、增强血糖控制和逆转肝脏脂肪变性方面被证明优于任何现有的双共激动剂和同类中最好的单激动剂。各种功能丧失模型，包括基因敲除、药理阻断和选择性化学敲除，都证实了体内每种成分活性的贡献。我们证明，这些单独的成分活动协调一致，以控制总体代谢效率，这主要是由于协同作用，以增加能量消耗，GLP-1作用，以减少卡路里摄入量和改善血糖控制，以及GIP作用，以加强内分泌作用和缓冲固有的高血糖素活动的糖尿病的影响；这些临床前研究表明，到目前为止，这种单分子，多药物策略可能是逆转肥胖和相关代谢紊乱的最有效的药理学方法。
We report the discovery of a new monomeric peptide that reduces body weight and diabetic complications in rodent models of obesity by acting as an agonist at three key metabolically-related peptide hormone receptors: glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and glucagon receptors. This triple agonist demonstrates supraphysiological potency and equally aligned constituent activities at each receptor, all without cross-reactivity at other related receptors. Such balanced unimolecular triple agonism proved superior to any existing dual coagonists and best-in-class monoagonists to reduce body weight, enhance glycemic control and reverse hepatic steatosis in relevant rodent models. Various loss-of-function models, including genetic knockout, pharmacological blockade and selective chemical knockout, confirmed contributions of each constituent activity in vivo. We demonstrate that these individual constituent activities harmonize to govern the overall metabolic efficacy, which predominantly results from synergistic glucagon action to increase energy expenditure, GLP-1 action to reduce caloric intake and improve glucose control, and GIP action to potentiate the incretin effect and buffer against the diabetogenic effect of inherent glucagon activity; These preclinical studies suggest that, so far, this unimolecular, polypharmaceutical strategy has potential to be the most effective pharmacological approach to reversing obesity and related metabolic disorders.