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GIPR:GCGR co-agonism restores normal weight in obese rodents.
Mol. Metab. 108:102365 (2026)
OBJECTIVE: Functional co- and tri-agonists at the receptors for GLP-1, GIP and glucagon effectively decrease body weight and hyperglycemia but are associated with adverse gastrointestinal effects related to GLP-1R agonism. Here we report the discovery that obesity can be reversed in the absence of a functional GLP-1R. It propelled the identification of a unimolecular GIPR:GCGR co-agonist lacking GLP-1 activity that corrects obesity in obese mice and rats. METHODS: Selective, dual, and triple sustained-action agonists at GIPR, GCGR and GLP-1R were used to assess body weight and glucose management in diet-induced obese (DIO) wildtype (WT) and GLP-1R knock-out (KO) mice. Indirect calorimetry and pair-feeding studies were used to characterize the magnitude of weight lowering specifically to suppression of food intake relative to energy expenditure. RESULTS: When used in physical co-mixture, selective GIPR agonism interacts with selective GCGR agonism to correct obesity and enhance glycemia in DIO mice. Retatrutide a balanced GLP-1R:GIPR:GCGR triagonist normalized body weight in obese GLP-1R KO mice. BWB3054, a fatty acylated GIPR:GCGR co-agonist, was identified as comparably potent as retatrutide to induce cAMP production at the mGIPR, and 4-fold reduced at mGCGR, but notably more than 100-fold diminished at mGLP-1R. Despite minimal relative GLP-1R potency, BWB3054 reduces excess body weight in obese DIO-mice to a similar degree as that observed for retatrutide in obese GLP-1R KO mice. CONCLUSIONS: Correction of obesity and glycemia in mice without employing GLP-1 agonism was demonstrated by three independent methods (GLP-1R KO with retatrutide, GIPR:GCGR physical co-agonism mixture, and GIPR:GCGR covalent co-agonist) which advocate for the prospect that the adverse GI effects commonly associated with its use might be avoided.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Gip ; Gipr:gcgr Co-agonism ; Glp-1 Free ; Glucagon ; Obesity ; Type 2 Diabetes; Glucagon-like Peptide-1; Glp-1 Receptor Agonist; Glycemic Control; Food-intake; Gip; Pharmacology; Physiology; Discovery; Rats
ISSN (print) / ISBN
2212-8778
e-ISSN
2212-8778
Journal
Molecular Metabolism
Quellenangaben
Volume: 108,
Article Number: 102365
Publisher
Elsevier
Publishing Place
Amsterdam
Reviewing status
Peer reviewed
Institute(s)
Institute of Diabetes and Obesity (IDO)
Grants
Indiana University
University of Cincinnati-College of Medicine
Blue Water Biosciences
University of Cincinnati-College of Medicine
Blue Water Biosciences