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

ABSTRACT 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 E 2 (PGE 2 ) EP4 signaling axis as a pivotal mediator linking gut dysbiosis to systemic insulin resistance. In obesity, elevated COX‐2‐derived PGE 2 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 PGE 2 –EP4 microbiota Treg network through EP4 antagonists or microbiome restoration offers a promising therapeutic strategy to restore metabolic balance and prevent obesity associated complications.