Prostaglandin E ₂ – EP4 Signaling at the Gut–Immune–Metabolic Interface: A Lipid Mediator Perspective on Obesity and Insulin Resistance

Despite advances in dietary and pharmacologic therapies, obesity rates continue to escalate globally. Emerging evidence implicates the gut-immune interface as a key determinant of metabolic dysfunction. This review highlights the prostaglandin E₂ (PGE₂) EP4 signaling axis as a pivotal mediator linking gut dysbiosis to systemic insulin resistance. In obesity, elevated COX-2-derived PGE₂ reprograms the gut microbiota, depleting short-chain fatty acid (SCFA)-producing taxa and reducing regulatory T cell (Treg) homeostasis. The ensuing loss of intestinal integrity promotes metabolic endotoxemia and chronic low-grade inflammation, culminating in insulin resistance. Targeting the PGE₂-EP4 microbiota Treg network through EP4 antagonists or microbiome restoration offers a promising therapeutic strategy to restore metabolic balance and prevent obesity associated complications.