Retatrutide

In preclinical diet-induced obese MASH mouse and hamster models, the triple GIP/GLP-1/glucagon receptor agonist retatrutide was reported to reduce body weight, hepatic steatosis and liver triglycerides, and HOMA-IR insulin resistance, with changes in food intake. Findings are limited to these animal models and do not establish human efficacy.

In this rodent study, the GLP-1R:GIPR:GCGR triagonist retatrutide was reported to normalize body weight in diet-induced obese GLP-1R-knockout mice, indicating retatrutide-driven weight reduction can occur without functional GLP-1 receptor signaling; a GIPR:GCGR co-agonist lacking GLP-1 activity lowered excess body weight comparably.

In a high-fat-diet mouse model, multi-omic profiling reported that the GIP/GLP-1/glucagon triple agonist retatrutide was associated with reduced adipose-tissue fibrosis — downregulated inflammatory/fibrotic pathways and upregulated reparative signaling — alongside metabolic reprogramming toward fatty-acid oxidation and improved mitochondrial function.

This review characterizes retatrutide (LY3437943) in the literature as a single-molecule triple receptor agonist acting on the GLP-1, GIP, and glucagon receptors, situating it within the broader development of multi-hormonal peptide pharmacology described for obesity and cardiometabolic comorbidities.