Bidirectional Pharmacology of GIP Receptor Targeting in Obesity: Historical Foundations, Mechanistic Divergence, and Translational Boundaries.

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.