Bidirectional pharmacology of GIP receptor targeting in obesity: Historical foundations, mechanistic divergence, and translational boundaries

IF 3.5 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides Pub Date : 2026-10-01 Epub Date: 2026-10-05 DOI:10.1016/j.peptides.2026.171524

Chenming Liu, Yanghai Wang, Jingli Liu, Peirong Tian, Jia Liu, Mengyi Li, Zhongtao Zhang, Peng Zhang

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引用次数: 0

Abstract

The glucose-dependent insulinotropic polypeptide receptor (GIPR) has emerged as a central target in next-generation anti-obesity drug development. Its pharmacology, however, presents an apparent paradox: sustained GIPR agonism and GIPR antagonism can both lower body weight, and both can augment weight loss produced by glucagon-like peptide-1 receptor (GLP-1R) agonism. For this structured narrative review, PubMed/MEDLINE and ClinicalTrials.gov were searched from database inception through 1 August 2026 using prespecified terms for receptors, interventions, obesity, and bariatric surgery to identify basic, translational, and clinical studies available. Retrieved records underwent staged title/abstract screening and full-text eligibility assessment. The evidence was integrated across three levels: selective GIPR modulation, combined GIPR and GLP-1R modulation, and applications after metabolic and bariatric surgery. Recent rodent studies support a working model in which long-acting GIPR agonism engages GABAergic and area-postrema-related circuits, whereas the added weight-lowering effect of GIPR antagonism in several GLP-1R-containing combination models depends on intact GLP-1R signaling and hypothalamic GIPR networks. These mechanisms remain incompletely validated in humans. Clinically, tirzepatide has demonstrated the efficacy of GIPR/GLP-1R co-agonism, whereas maridebart cafraglutide provides phase 2 evidence for GIPR antagonism combined with GLP-1R agonism; nevertheless, the efficacy of these multi-receptor agents cannot be attributed simply to a single GIPR component. Metabolic and bariatric surgery is discussed as a translational context in which altered incretin physiology limits direct extrapolation from nonsurgical obesity trials. Future studies should use stratified designs grounded in receptor pharmacology, brain-region specificity, type of bariatric procedure, and postoperative metabolic phenotype, while assessing fat mass, lean mass, hepatic fat, bone metabolism, gastrointestinal tolerability, hypoglycemia, and weight regain after treatment withdrawal.

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肥胖中GIP受体靶向的双向药理学：历史基础、机制分歧和翻译边界。

葡萄糖依赖性胰岛素多肽受体（GIPR）已成为下一代抗肥胖药物开发的中心靶点。然而，其药理学表现出明显的矛盾：持续的GIPR激动作用和GIPR拮抗作用都可以降低体重，并且都可以增加胰高血糖素样肽-1受体（GLP-1R）激动作用产生的体重减轻。对于这篇结构化的叙事性综述，PubMed/MEDLINE和ClinicalTrials.gov从数据库建立到2026年8月1日，使用预设的受体、干预、肥胖和减肥手术术语进行检索，以确定可用的基础、转化和临床研究。检索到的记录进行分阶段的标题/摘要筛选和全文合格性评估。证据整合在三个层面：选择性GIPR调节，GIPR和GLP-1R联合调节，以及代谢和减肥手术后的应用。最近的啮齿动物研究支持一种工作模型，其中长效GIPR拮抗剂参与gaba能和区域-脑后相关回路，而在几种含有GLP-1R的组合模型中，GIPR拮抗剂的额外减肥效果依赖于完整的GLP-1R信号传导和下丘脑GIPR网络。这些机制在人类中仍未完全得到证实。临床研究表明，替西帕肽具有GIPR/GLP-1R联合拮抗作用，而卡拉格鲁肽具有GIPR联合GLP-1R拮抗作用的2期证据；然而，这些多受体药物的功效不能仅仅归因于单一的GIPR成分。代谢和减肥手术作为一种翻译背景进行讨论，其中肠促胰岛素生理学的改变限制了非手术肥胖试验的直接推断。未来的研究应采用基于受体药理学、脑区特异性、减肥手术类型和术后代谢表型的分层设计，同时评估脂肪量、瘦质量、肝脂肪、骨代谢、胃肠道耐受性、低血糖和停药后体重恢复。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Peptides 医学-生化与分子生物学

CiteScore

6.40

自引率

6.70%

发文量

130

审稿时长

28 days

期刊介绍： Peptides is an international journal presenting original contributions on the biochemistry, physiology and pharmacology of biological active peptides, as well as their functions that relate to gastroenterology, endocrinology, and behavioral effects. Peptides emphasizes all aspects of high profile peptide research in mammals and non-mammalian vertebrates. Special consideration can be given to plants and invertebrates. Submission of articles with clinical relevance is particularly encouraged.