Multi-omic profiling reveals Retatrutide alleviates adipose tissue fibrosis via metabolic reprogramming and tissue repair.

BACKGROUND: Retatrutide, a novel GIP, GLP-1, and glucagon receptor triple agonist, exhibits unprecedented weight-reducing efficacy in clinical trials, yet the molecular basis of its systemic metabolic benefits remains unclear. METHODS: Using a high-fat diet–induced obesity mouse model, we investigated the effects of Retatrutide on adipose tissue through integrated physiological, histological, transcriptomic, and metabolomic analyses. RESULTS: Retatrutide markedly reduced body weight and adiposity and improved metabolic parameters including glucose homeostasis and dyslipidemia. Multi-omic profiling revealed a coordinated reprogramming of epididymal white adipose tissue, characterized by suppressed lipogenesis, enhanced fatty acid oxidation and mitochondrial function, restored peroxisomal activity, and downregulated inflammatory/fibrotic pathways while promoting angiogenic/reparative signaling. Metabolomic analysis further demonstrated clearance of lipotoxic intermediates, decreased pro-inflammatory lipids, reduced collagen-derived metabolites, and elevated anti-inflammatory 15-HETE, confirming metabolic restoration at multiple regulatory levels. CONCLUSIONS: Retatrutide transforms dysfunctional white adipose tissue into a metabolically competent organ by simultaneously enhancing lipid oxidation, suppressing inflammation and fibrotic remodeling, and restoring endocrine function. These findings identify adipose tissue as an important therapeutic target of triple incretin agonism and establish tissue quality restoration—rather than mere mass reduction—as a new therapeutic paradigm for obesity and related metabolic disorders.