Prostaglandins (PGs) have long been suggested to regulate adipocyte differentiation and function. However, these studies were mainly based on in vitro culture systems, and there have been no reports that genetic deletion of PG-producing enzymes or PG receptors affects adipose tissue weight, so it is unclear whether PG regulates adipocyte differentiation and fat accumulation in actual adipose tissue in vivo. By systematically analyzing eight types of PG receptor-deficient mice, we found that EP4 receptor deficiency, one of the PGE₂ receptors, leads to a "metabolically healthy obese" phenotype in which white adipose tissue (WAT) weight is increased under normal diet conditions, but insulin sensitivity is enhanced. Various analyses revealed that PGE₂ is produced from arachidonic acid generated by lipolysis in WAT and binds to EP4 receptors as an autocrine receptor, thereby negatively regulating insulin action. In this symposium, we would like to discuss the significance of the regulation of lipid metabolism by PGE₂-EP4 receptor signaling in WAT and the possibility that this PGE₂-EP4 pathway is also involved in lipid metabolism in humans.