Prostaglandin E2-EP4 Axis Promotes Lipolysis and Fibrosis in Adipose Tissue Leading to Ectopic Fat Deposition and Insulin Resistance

Lipolysis, the breakdown of triglyceride storage in white adipose tissue, supplies fatty acids to other tissues as a fuel under fasting conditions. In morbid obesity, fibrosis limits adipocyte expandability, resulting in enforced lipolysis, ectopic fat distribution, and ultimately insulin resistance. Although basal levels of lipolysis persist even after feeding, the regulatory mechanisms of basal lipolysis remain unclear. Here, we show the important role of adipocyte prostaglandin (PG) E2-EP4 receptor signaling in controlling basal lipolysis, fat distribution, and collagen deposition during feeding-fasting cycles. The PGE2-synthesis pathway in adipocytes, which is coupled with lipolysis, is activated by insulin during feeding. By regulating the lipolytic key players, the PGE2-EP4 pathway sustains basal lipolysis as a negative feedback loop of insulin action, and perturbation of this process leads to “metabolically healthy obesity.” The potential role of the human EP4 receptor in lipid regulation was also suggested through genotype-phenotype association analyses. [Display omitted] •Adipocyte EP4 sustains basal lipolysis by negative feedback of insulin action•EP4 promotes WAT fibrosis by the specific induction of type 6 collagen expression•Prostaglandin E2 synthesis in WAT is coupled to lipolysis and activated by insulin•Perturbation of EP4 action in adipocytes leads to “metabolically healthy obesity” Fasting and cold stress are well-known facilitators of lipolysis in WAT, but it remains unclear whether there are other physiological mechanisms that regulate lipolysis. Inazumi et al. find that the adipocyte prostaglandin E2-EP4 receptor axis controls basal lipolysis, fat distribution, and collagen deposition upon feeding and insulin stimuli.