From dual to quintuple agonism for next-generation pharmacology to treat obesity and type 2 diabetes: synergistic incretin and nuclear receptor signaling.

Receptor-targeted polypharmacology is emerging as a promising strategy for the treatment of obesity, type 2 diabetes, and metabolic dysfunction-associated steatohepatitis. GLP-1-GIP-lanifibranor, a unimolecular conjugate combining GLP-1R/GIPR co-agonism with pan-PPAR activation, enables receptor-guided intracellular delivery of lanifibranor to incretin receptor-expressing cells while limiting systemic off-target exposure. In obese mouse models, the conjugate produced greater reductions in body weight, adiposity, food intake, and hyperglycemia than semaglutide, GLP-1-GIP co-agonism, or lanifibranor alone, while significantly improving insulin sensitivity. Mechanistic analyses demonstrated receptor-dependent delivery and identified PPARδ signaling as a principal mediator of glycemic improvement independent of weight loss. Unlike unconjugated lanifibranor, the conjugate did not induce anemia, fluid retention, renal dysfunction, or adipocyte differentiation, supporting the concept that tissue-restricted PPAR activation may mitigate classical adverse effects of systemic PPAR agonism. These findings establish peptide-directed nuclear receptor targeting as a potentially important platform for next-generation metabolic therapeutics, although substantial translational uncertainties remain regarding clinical efficacy, safety, and long-term applicability.