Inhibition of phosphodiesterase type 9 reduces obesity and cardiometabolic syndrome in mice

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) in both ovariectomized female or male mice suppresses pre-established severe diet-induced obesity/CMS with or without superimposed mild cardiac pressure-load. PDE9-I reduces total body, inguinal, hepatic, and myocardial fat, stimulating mitochondrial activity in brown and white fat, and improving CMS, without significantly altering activity or food intake. PDE9 localized at mitochondria, and its inhibition in vitro stimulated lipolysis and mitochondrial respiration in adipocytes and myocytes coupled to PPARa-dependent gene regulation.PPARa upregulation was required to achieve the lipolytic, anti-obesity, and metabolic effects of PDE9-I. All these PDE9-I induced changes were not observed in obese/CMS non-ovariectomized females, indicating a strong sexual dimorphism. We found that PPARa chromatin binding was re-oriented away from fat-metabolism regulating genes when stimulated in the presence of co-activated estrogen receptor-a, and this may underly the dimorphism. These findings have translational relevance given that PDE9-I is already being studied in humans for indications including heart failure, and efficacy against obesity/CMS would enhance its therapeutic utility.

Riociguat attenuates the changes in left ventricular proteome and microRNA profile after experimental aortic stenosis in mice

“…Such inhibition of PDE 9A reduced hypertrophy, fibrosis and corresponding molecular signalling. Further, this work also showed that inhibition of PDE 9A increased mitochondrial respiration and fatty acid oxidation also in cardiomyocytes in vitro(Mishra et al, 2021). These findings are in line with our results of improved metabolism and energy production after riociguat treatment in TAC, which further supports the evidence of beneficial effects from different strategies of cGMP augmentation in different settings of CVD.…”

Phosphodiesterases and Compartmentation of cAMP and cGMP Signaling in Regulation of Cardiac Contractility in Normal and Failing Hearts

“…PDE9A is the PDE with the lowest K m for cGMP (0.70-0.17 µM) and it was recently discovered to be expressed in the heart, localized to the SR (but not Z-disc, where PDE5 was located), and regulating cGMP generated after GC-A stimulation, but not from stimulating sGC [2,105]. Moreover, PDE9 is localized in the mitochondria in cardiomyocytes [111]. We are not aware of any literature where PDE9 inhibition regulates cGMP-mediated contractility.…”

BAY-7081: A Potent, Selective, and Orally Bioavailable Cyanopyridone-Based PDE9A Inhibitor

“…PDE9A expression has been reported for various tissues including those of the kidney − and the heart. , Furthermore, the recent literature suggests that inhibiting PDE9A might be beneficial for the treatment of renal dysfunction, HFrEF , and HFpEF. , We therefore studied urinary cGMP in rats and functional parameters in a rat heart failure model after PDE9A inhibition.…”