Despite sharing incretin activity with glucagon-like peptide 1 (GLP-1), the development of gastric inhibitory polypeptide (GIP)-based drugs has been hindered by the minor effects of native GIP on appetite and body weight and genetic studies associating loss-of-function with reduced obesity. Yet, pharmacologically optimized GIP-based molecules have demonstrated profound weight lowering benefits of GIPR agonism when combined with GLP-1-based therapies, which has re-energized deeper exploration of the molecular mechanisms and downstream signaling of GIPR. Interestingly, both GIPR agonism and antagonism offer metabolic benefits, leading to differing viewpoints on how to target GIPR therapeutically. Here we summarize the emerging evidence about the tissue-specific mechanisms that positions GIP-based therapies as important targets for the next generation of anti-obesity and metabolic therapies.

中文翻译：

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GIP 在改变肥胖治疗方面发挥着意想不到的作用。


尽管与胰高血糖素样肽 1 (GLP-1) 具有相同的肠促胰素活性，但基于胃抑制多肽 (GIP) 的药物的开发受到天然 GIP 对食欲和体重的轻微影响以及与胃抑制多肽相关的遗传研究的阻碍。 - 减少肥胖的功能。然而，药理优化的基于 GIP 的分子已经证明，当与基于 GLP-1 的疗法相结合时，GIPR 激动剂具有显着的减肥功效，这重新激发了对 GIPR 分子机制和下游信号传导的更深入探索。有趣的是，GIPR 激动和拮抗都具有代谢益处，导致对于如何靶向 GIPR 治疗存在不同观点。在这里，我们总结了有关组织特异性机制的新证据，这些证据将基于 GIP 的疗法定位为下一代抗肥胖和代谢疗法的重要目标。