Objective

Glucose-dependent insulinotropic polypeptide is an intestinally derived hormone that is essential for normal metabolic regulation. Loss of the GIP receptor (GIPR) through genetic elimination or pharmacological antagonism reduces body weight and adiposity in the context of nutrient excess. Interrupting GIPR signaling also enhances the sensitivity of the receptor for the other incretin peptide, glucagon-like peptide 1 (GLP-1). The role of GLP-1 compensation in loss of GIPR signaling to protect against obesity has not been directly tested.

Methods

We blocked the GIPR and GLP-1R with specific antibodies, alone and in combination, in healthy and diet-induced obese (DIO) mice. The primary outcome measure of these interventions was the effect on body weight and composition.

Results

Antagonism of either the GIPR or GLP-1R system reduced food intake and weight gain during high-fat feeding and enhanced sensitivity to the alternative incretin signaling system. Combined antagonism of both GIPR and GLP-1R produced additive effects to mitigate DIO. Acute pharmacological studies using GIPR and GLP-1R agonists demonstrated both peptides reduced food intake, which was prevented by co-administration of the respective antagonists.

Conclusions

Disruption of either axis of the incretin system protects against diet-induced obesity in mice. However, combined antagonism of both GIPR and GLP-1R produced additional protection against diet-induced obesity, suggesting additional factors beyond compensation by the complementary incretin axis. While antagonizing the GLP-1 system decreases weight gain, GLP-1R agonists are used clinically to target obesity. Hence, the phenotype arising from loss of function of GLP-1R does not implicate GLP-1 as an obesogenic hormone. By extension, caution is warranted in labeling GIP as an obesogenic hormone based on loss-of-function studies.

中文翻译：

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肠降血糖素系统的药理拮抗作用可防止饮食引起的肥胖。

客观的

葡萄糖依赖性促胰岛素多肽是肠道衍生的激素，对于正常的代谢调节至关重要。在营养过量的情况下，通过遗传消除或药理拮抗作用使GIP受体（GIPR）丢失，从而减轻了体重和肥胖。中断GIPR信号传导还增强了受体对其他肠降血糖素肽，胰高血糖素样肽1（GLP-1）的敏感性。尚未直接测试过GLP-1补偿在GIPR信号丢失中保护肥胖的作用。

方法

我们在健康和饮食诱发的肥胖（DIO）小鼠中单独或联合使用特异性抗体阻断了GIPR和GLP-1R。这些干预措施的主要结局指标是对体重和组成的影响。

结果

GIPR或GLP-1R系统的拮抗作用可减少高脂喂养期间的食物摄入和体重增加，并增强对替代性肠降血糖素信号传导系统的敏感性。GIPR和GLP-1R的联合拮抗作用产生加和效应，以减轻DIO。使用GIPR和GLP-1R激动剂进行的急性药理研究表明，这两种肽均减少了食物摄入，这是通过共同施用相应的拮抗剂来防止的。

结论

肠降血糖素系统任一轴的破坏可防止小鼠饮食引起的肥胖。但是，GIPR和GLP-1R的联合拮抗作用可抵抗饮食引起的肥胖症，从而提供了额外的保护作用，这表明除了补充肠降血糖素轴外，还存在其他因素。拮抗GLP-1系统可减轻体重增加，而GLP-1R激动剂在临床上可用于治疗肥胖症。因此，由GLP-1R功能丧失引起的表型并不暗示GLP-1是致肥胖激素。进一步地，基于功能丧失研究，在将GIP标记为致肥胖激素时，应谨慎行事。