Inhibiting the prostaglandin transporter PGT induces non-canonical thermogenesis at thermoneutrality

ABSTRACT / SUMMARY Prostaglandins play fundamental roles in adipose tissue function. While prostaglandin F 2α inhibits adipogenesis, prostaglandin E 2 promotes adipose beiging. PGF 2α and PGE 2 are both inactivated through uptake by the plasma membrane transporter (PGT). We hypothesized that inhibiting PGT would increase PGF 2α and PGE 2 levels, thereby reducing white fat expansion and inducing beiging. Consistent with this hypothesis, inhibiting PGT in mice on high fat diet via genetic knockout or pharmacological blockade reduced body fat stores and induced thermogenesis at thermoneutrality. Inguinal white adipose tissue (iWAT) of these mice exhibited robust UCP1-independent thermogenesis characterized by mitochondrial expansion, coupling of O 2 consumption to ATP synthesis, and induction of the creatine pathway. Enhanced coupled respiration persisted in PGT-KO iWAT adipocytes in a creatine shuttle-dependent manner. Thus, inhibiting PGT increases mitochondrial biogenesis and coupled respiration—each supported by the creatine pathway in a system lacking UCP1 expression—revealing PGT as a promising drug target against obesity.