A New Chapter in Obesity Treatment: Mechanisms and Clinical Research Progress of Multi-target Peptide Agonists

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 for 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.