Retatrutide (a multi-receptor peptide agonist designed to engage GLP-1, GIP and glucagon receptor families) represents an evolution in polypharmacology aimed at coordinated modulation of metabolic signaling axes. Preclinical and translational reviews describe how combined receptor agonism can produce synergistic effects on energy balance and hepatic metabolism in animal and in vitro systems, and mechanistic work has focused on receptor pharmacology, biased signaling, and how concurrent activation of incretin and glucagon pathways alters substrate fluxes and tissue-level signaling networks. These mechanistic studies are important for interpreting nonclinical efficacy signals and for mapping receptor-specific contributions in experimental models

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