PDE9 Inhibition Activates PPARα to Stimulate Mitochondrial Fat Metabolism and Reduce Cardiometabolic Syndrome

Abstract

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 PPARa dependent gene regulation. PPARa 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-a altering PPARa 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.

Increased Energy Expenditure and Protection From Diet-Induced Obesity in Mice Lacking the cGMP-Specific Phosphodiesterase PDE9

“…Most importantly, current studies indicate they are safe and well tolerated in humans ( 28 – 34 ). Moreover, analogous to what we show in this study with Pde9a −/− mice, our collaborators have found that the PF PDE9 inhibitor reduces body weight by increasing energy expenditure and thereby improves glucose handling in a model of cardiometabolic disease ( 50 ). Comparable to our findings, the results of Mishra et al ( 50 ) show that PDE9 inhibition is associated with increased respiration and expression of thermogenic genes including Ucp1 ( 50 ).…”

“…Moreover, analogous to what we show in this study with Pde9a −/− mice, our collaborators have found that the PF PDE9 inhibitor reduces body weight by increasing energy expenditure and thereby improves glucose handling in a model of cardiometabolic disease ( 50 ). Comparable to our findings, the results of Mishra et al ( 50 ) show that PDE9 inhibition is associated with increased respiration and expression of thermogenic genes including Ucp1 ( 50 ). Together, these observations suggest that PDE9 inhibitors can increase thermogenic gene expression in adipocytes via increasing PKG signaling, and these therapeutic implications may be translatable to humans.…”

Device-Based Solutions to Improve Cardiac Physiology and Hemodynamics in Heart Failure With Preserved Ejection Fraction

“…A multitude of trials have studied the effects of up-regulating cGMP synthesis through inorganic nitrates in HFpEF or of other agents such as soluble guanylate cyclase stimulators (eg, vericiguat, praliciguat) ( 56 , 57 , 58 ). In addition, the effects of phosphodiesterase type 5 and 9 inhibition have also been investigated ( 59 , 60 ). To date, however, none of these pathways has shown clinical benefit in patients with HFpEF.…”