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Sex-Dependent Obesity Reduction from PPARa Activation by PDE9 Inhibition

ABSTRACT: The ongoing pandemics of obesity and hypertension have increasingly impacted an aging population with heart disease creating a prevalent cardiometabolic syndrome (CMS). This affects many post-menopausal women and men and manifests by multi-organ adiposity, insulin desensitization and diabetes, impaired fat metabolism, and heart failure symptoms. Effective therapy countering these multiple defects remains lacking. Natriuretic peptides (NP) synthesized by the heart both protect against cardiac disease and reduce obesity by stimulating lipolysis, improving insulin signaling, and lowering appetite. However, their clinical translation remains stymied by blood pressure reduction and complex in vivo peptide pharmacology. Phosphodiesterase type 9 is expressed in myocardium and fat of mammals including humans and controls NP-coupled cyclic GMP hydrolysis. Its inhibition (PDE9-I) protects hearts against pressure-induced stress without changing blood pressure, though its impact on fat remains unknown. Here we show PDE9-I potently improves high-fat diet-induced severe obesity in mice with cardiometabolic syndrome without altering food intake or activity, but this only occurs in males and ovariectomized females. PDE9 localizes with mitochondria and its inhibition stimulates mitochondrial respiration, uncoupling, and fat oxidation in heart and adipose tissue to reduce abdominal and liver fat by activating peroxisome proliferator-activator receptor a (PPARa) signaling. ChIP-seq reveals that the sexual dimorphism relates to reduced PPARa DNA binding in genes regulating fatty acid metabolism due to estrogen-receptor activation. Human translation is revealed in obese patients with heart failure and preserved ejection fraction (HFpEF), in whom PDE9A and PPARA gene expression inversely correlate, and PPARA and fat metabolism regulated genes are reduced. This potent PDE9-PPARa regulated pathway has implications for treating obese post-menopausal females and males with cardiometabolic syndrome. HFpEF accounts for half of all heart failure and is now commonly associated with class II (BMI>35 kg/m2) or greater obesity and CMS. The obesity is particularly hard to treat in these patients given that exercise capacity is quite limited, diet is rarely impactful at such weight, and surgical therapy poses greater risks. Despite having heart disease, NP levels are often low as hearts are less dilated and there is greater peripheral clearance with obesity. Loss of estrogen after menopause increases female risks for cardiovascular disease and stimulates visceral adiposity. Ovariectomy (OVX) mimics these changes, and when combined with a high-fat diet, exacerbates adiposity and adverse consequences of ischemic and hypertensive stress. These are reversed by exogenous estrogen but not therapies that require intact nitric oxide signaling, revealing an important role of estrogen-NO pathways. Estrogen treatment is largely abandoned due to adverse effects in humans. However, PDE9-I elevates cGMP-signaling by the NP pathway independent of NO-stimulation. We hypothesized that PDE9-I retains cardiac benefits in OVX female hearts subjected to pressure-induced stress and may also stimulate fat loss to improve CMS in concomitant diet induced obesity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE156956 | GEO | 2023/08/31

REPOSITORIES: GEO

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Sex-Dependent Obesity Reduction from PPARa Activation by PDE9 Inhibition

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