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