Background

Glucose-dependent insulinotropic peptide (GIP) is one of two incretin hormones that communicate nutrient intake with systemic metabolism. Although GIP was the first incretin hormone to be discovered, the understanding of GIP biology was quickly outpaced by the research focusing on the other incretin hormone, glucagon-like peptide 1 (GLP-1). Early work on GIP produced the notion that GIP is obesogenic, limiting the interest in developing GIPR agonists for the treatment of type 2 diabetes. A resurgence of GIP research has taken place in the last five years, reinvigorating interest in this peptide. Interestingly, two independent approaches have emerged for the treatment of obesity, one promoting GIPR agonism and the other antagonism. Here, the evidence supporting both cases are discussed and hypotheses are presented to reconcile this apparent paradox.

Scope of the Review

This review presents the evidence to support the targeting of the GIPR as a means to reduce obesity. Most of the focus is on the effect of singly targeting the GIPR in both a gain- and loss-of-function approach, with additional sections that discuss co-targeting of the GIPR and GLP-1R.

Major Conclusions

There is substantial evidence to support that both GIPR agonism and antagonism can positively impact body weight. The long-standing notion that GIP drives weight gain is exclusively derived from loss-of-function studies, with no evidence to support that GIPR agonisms increases adiposity or body weight. There is insufficient evidence to reconcile the paradoxical observations that both GIPR agonism and antagonism can reduce body weight, however, two independent hypotheses centered on GIPR antagonism are presented based on new data in an effort to address this question. The first discusses the compensatory relationship between incretin receptors and how antagonism of the GIPR may enhance GLP-1R activity. The second discusses how chronic GIPR agonism may produce desensitization and ultimately loss of GIPR activity that mimics antagonism. Overall, it is clear that a deeper understanding of GIP biology is required in order to understand how modulating this system impacts metabolic homeostasis.

中文翻译：

---

针对肥胖症的 GIPR：痛苦还是对抗？潜在机制

背景

葡萄糖依赖性促胰岛素肽 (GIP) 是两种肠促胰岛素激素之一，可将营养摄入与全身代谢联系起来。尽管 GIP 是第一个被发现的肠促胰岛素激素，但对 GIP 生物学的理解很快就被专注于另一种肠促胰岛素激素、胰高血糖素样肽 1 (GLP-1) 的研究所超越。GIP 的早期工作产生了 GIP 致肥胖的概念，限制了开发用于治疗 2 型糖尿病的 GIPR 激动剂的兴趣。GIP 研究在过去五年中重新兴起，重新激发了人们对这种肽的兴趣。有趣的是，出现了两种独立的治疗肥胖的方法，一种促进 GIPR 激动，另一种拮抗。在这里，讨论了支持这两种情况的证据，并提出了假设来调和这一明显的悖论。

审查范围

本综述提供的证据支持将 GIPR 作为减少肥胖的手段。大多数重点是在功能获得和功能丧失的方法中单独靶向 GIPR 的影响，还有其他部分讨论了 GIPR 和 GLP-1R 的共同靶向。

主要结论

有大量证据支持 GIPR 激动和拮抗均可对体重产生积极影响。GIP 驱动体重增加的长期观点完全来自功能丧失研究，没有证据支持 GIPR 激动剂会增加肥胖或体重。没有足够的证据来调和 GIPR 激动和拮抗都可以减轻体重的矛盾观察结果，但是，基于新数据提出了两个以 GIPR 拮抗为中心的独立假设，以解决这个问题。第一个讨论了肠促胰岛素受体之间的补偿关系以及 GIPR 的拮抗作用如何增强 GLP-1R 活性。第二部分讨论了慢性 GIPR 激动如何导致脱敏并最终丧失模拟拮抗作用的 GIPR 活性。总体，