Central obesity with cardiometabolic syndrome (CMS) is a major global contributor to human disease, and effective therapies are needed. Here, we show inhibiting cyclic-GMP selective phosphodiesterase-9A (PDE9-I) suppresses established diet-induced obesity and CMS in ovariectomized female and male mice. PDE9-I reduces abdominal, hepatic, and myocardial fat accumulation, stimulates mitochondrial activity in brown and white fat, and improves CMS, without altering activity or food intake. PDE9 localizes to mitochondria, and its inhibition stimulates lipolysis and mitochondrial respiration coupled to PPARα-dependent gene regulation. PPARα upregulation is required for PDE9-I metabolic efficacy and is absent in non-ovariectomized females that also display no metabolic benefits from PDE9-I. The latter is compatible with estrogen receptor-α altering PPARα chromatin binding identified by ChIPSeq. In humans with heart failure and preserved ejection fraction, myocardial expression of PPARA and its regulated genes is reduced versus control. These findings support testing PDE9-I to treat obesity/CMS in men and postmenopausal women.

Oral inhibition of phosphodiesterase type 9 stimulates mitochondrial fat metabolism and lipolysis, reducing central obesity without changing appetite