A new glucagon and GLP-1 co-agonist eliminates obesity in rodents
A new glucagon and GLP-1 co-agonist eliminates obesity in rodents
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DOI：
10.1038/nchembio.209
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发表时间：
2009-10-01
影响因子：
14.8
通讯作者：
Tschoep, Matthias H.
中科院分区：
文献类型：
--
作者：
Day, Jonathan W.;Ottaway, Nickki;Tschoep, Matthias H.
我们报道了一种对胰高血糖素和GLP-1受体具有激动作用的新肽的功效，这种肽具有有效的、持续的饱腹感诱导和脂溶作用。选择性化学修饰胰高血糖素导致特异性的丧失，对固有活性的改变很小。共激动作用的结构基础似乎是局部位置相互作用和二级结构变化的结合。在啮齿动物肥胖模型中研究了两种仅在胰高血糖素受体激动作用水平上不同的共激动剂肽。每周一次给药聚乙二醇化肽使饮食诱导的肥胖小鼠的肥胖和葡萄糖耐量正常化。体重的减轻是通过减少食物摄入和增加能量消耗而导致的体脂损失来实现的。这些临床前研究表明，当充分的GLP-1激动作用被适当程度的胰高血糖素受体激活时，体脂减少可以显著增强，而没有任何明显的不良反应。
We report the efficacy of a new peptide with agonism at the glucagon and GLP-1 receptors that has potent, sustained satiation-inducing and lipolytic effects. Selective chemical modification to glucagon resulted in a loss of specificity, with minimal change to inherent activity. The structural basis for the co-agonism appears to be a combination of local positional interactions and a change in secondary structure. Two co-agonist peptides differing from each other only in their level of glucagon receptor agonism were studied in rodent obesity models. Administration of PEGylated peptides once per week normalized adiposity and glucose tolerance in diet-induced obese mice. Reduction of body weight was achieved by a loss of body fat resulting from decreased food intake and increased energy expenditure. These preclinical studies indicate that when full GLP-1 agonism is augmented with an appropriate degree of glucagon receptor activation, body fat reduction can be substantially enhanced without any overt adverse effects.