Abstract: Obesity is a chronic and relapsing disease resulting from interactions between genetic and environmental factors. Its global prevalence continues to rise, making it a major public health challenge. Traditional weight management strategies often yield suboptimal outcomes. In recent years, peptide-based therapies targeting the glucagon-like peptide-1 receptor (GLP-1R), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon receptor (GCGR) have advanced rapidly, with multi target agonists emerging as a promising new therapeutic trend. This review systematically summarizes the mechanisms and clinical progress of these agents: GLP-1R single-target agonists demonstrate significant efficacy in weight reduction, glycemic control, and multi-organ protection, though interindividual variability and gastrointestinal side effects remain limitations. Dual agonists targeting GLP-1R/GIPR and GLP-1R/GCGR (e.g., Tirzepatide, Mazdutide) further improve metabolic parameters, reduce liver fat, and mitigate cardiovascular risks through synergistic regulation of appetite, energy expenditure, and lipid metabolism. Meanwhile, the triple agonist Retatrutide (targeting GLP-1R/GIPR/GCGR) shows robust potential in weight loss and body composition improvement, while also modulating key lipid metabolic regulators such as ANGPTL3/8, thereby broadening the therapeutic horizon for metabolic diseases. Looking forward, the development of multi-target agents—combined with long-acting formulation technologies, precise subtyping, and individualized treatment strategies—is expected to significantly enhance the efficacy and safety of obesity treatments and alleviate the public health burden.

Key words: Obesity, Multi-target peptide agonists, Glucagon-like peptide-1 receptor, Glucose-dependent insulinotropic polypeptide receptor, Glucagon receptor

摘要： 肥胖症是一种由遗传与环境因素交互作用导致的慢性、复发性疾病，全球患病率持续上升，已成为重大公共卫生挑战。传统体重管理策略效果有限，近年来以胰高血糖素样肽 -1 受体（GLP-1R）、葡萄糖依赖性促胰岛素多肽受体（GIPR）和胰高血糖素受体（GCGR）为靶点的肽类药物快速发展，尤其多靶点激动剂逐渐成为治疗新趋势。本文系统介绍了该类药物的作用机制与临床研究进展：GLP-1R 单靶点激动剂在减重、降糖及多器官保护中显示显著效果，但仍存在个体差异和胃肠道不良反应；GLP-1R/GIPR 及 GLP-1R/GCGR 双靶点激动剂（如替尔泊肽、玛仕度肽）通过协同调控摄食、能量消耗和脂代谢，进一步改善代谢指标并减轻肝脏脂肪及心血管风险；而GLP-1R/GIPR/GCGR三重激动剂瑞他鲁肽更展现出强劲的减重与身体成分优化潜力，同时调节 ANGPTL3/8 等脂代谢关键因子，拓宽了代谢性疾病的治疗前景。展望未来，多靶点药物研发结合长效制剂技术、精准分型及个体化治疗策略，有望显著提升肥胖症的治疗效果与用药安全性，减轻公共健康负担。

关键词: 肥胖症, 多靶点肽类激动剂, 胰高血糖素样肽 -1 受体, 葡萄糖依赖性促胰岛素多肽受体, 胰高血糖素受体