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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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Project description:The global prevalence of obesity is increasing across age and gender. The rising burden of obesity in young people contributes to the early emergence of type 2 diabetes. Having one parent obese is an independent risk factor for childhood obesity. While the detrimental impact of diet-induced maternal obesity on offspring is well established, the extent of the contribution of obese fathers is unclear, as is the role of non-genetic factors in the casual pathway. Here we show that paternal high fat diet exposure programmed Î²-cell âdysfunctionâ in their F1 female offspring. Chronic high fat diet consumption in Sprague Dawley fathers led to increased body weight, adiposity, impaired glucose tolerance and insulin sensitivity. Relative to controls, their female offspring had lower body weight at day-1, increased pubertal growth rate, impaired insulin secretion and glucose tolerance, in the absence of obesity or increased adiposity. Paternal high fat diet was observed to alter gene expression of pancreatic islet genes in adult female offspring (P < 0.001); affected functional clusters includes calcium ion binding, insulin, apoptosis, Wnt and cell cycle organ/system development. This is the first reported study in mammals describing non-genetic, intergenerational transmission of metabolic sequelae of high fat diet from father to offspring. These findings support a role of fathers in metabolic programming of offspring and form a framework for further studies. F0 founders were male Sprague Dawley rats, divided into two groups, high fat (HF) and control. The HF fathers were given commercially prepared high-fat pellets (43% as fat); while the controls ate standard laboratory chow (9% as fat). The two groups of fathers had distinct phenotype; the HF fathers were significantly heavier with increased adiposity, they were also glucose intolerant and insulin resistant. At 15 weeks of age, fathers were mated with normal females consuming chow, to generate the F1 offspring. Only female offspring were studied. Female offspring were weaned unto standard laboratory chow at 3 weeks. At 6 and 12 weeks, intraperitoneal glucose tolerance test (IpGTT) was performed to measure blood glucose and insulin profile; at 11 weeks, intraperitoneal insulin tolerance test was done. The body weight and adiposity of these offspring were not different between the two groups. The HF offspring had glucose intolerance and impaired glucose-induced insulin response, mainly at the acute phase, observed since 6 weeks. The IpITT was not different between groups. At 13 weeks, islets were harvested from the two groups of offspring.

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Project description:The global prevalence of obesity is increasing across age and gender. The rising burden of obesity in young people contributes to the early emergence of type 2 diabetes. Having one parent obese is an independent risk factor for childhood obesity. While the detrimental impact of diet-induced maternal obesity on offspring is well established, the extent of the contribution of obese fathers is unclear, as is the role of non-genetic factors in the casual pathway. Here we show that paternal high fat diet exposure programmed M-NM-2-cell M-bM-^@M-^XdysfunctionM-bM-^@M-^Y in their F1 female offspring. Chronic high fat diet consumption in Sprague Dawley fathers led to increased body weight, adiposity, impaired glucose tolerance and insulin sensitivity. Relative to controls, their female offspring had lower body weight at day-1, increased pubertal growth rate, impaired insulin secretion and glucose tolerance, in the absence of obesity or increased adiposity. Paternal high fat diet altered the expression of 211 pancreatic islet genes in adult female offspring (P < 0.001); genes belonged to 8 functional clusters, including calcium ion binding, primary metabolic processes and ATP binding, and organ/system development. Broader KEGG pathway analysis of 2014 genes differentially expressed at the P < 0.01 level further demonstrated involvement of insulin and calcium signaling, and MAPK pathways. This is the first reported study in mammals describing non-genetic, intergenerational transmission of metabolic sequelae of high fat diet from father to offspring. These findings support a role of fathers in metabolic programming of offspring and form a framework for further studies. F0 founders were male Sprague Dawley rats, divided into two groups: high fat (HF) and control. The HF fathers were given commercially prepared high-fat pellets (43% as fat), while the controls ate standard laboratory chow (9% as fat). The two groups of fathers had distinct phenotypes; the HF fathers were significantly heavier with increased adiposity, and they were also glucose intolerant and insulin resistant. At 15 weeks of age, fathers were mated with normal females consuming chow to generate the F1 offspring. Only female offspring were studied. Female offspring were weaned unto standard laboratory chow at 3 weeks. At 6 and 12 weeks, an intraperitoneal glucose tolerance test (IpGTT) was performed to measure blood glucose and insulin profile; at 11 weeks, an intraperitoneal insulin tolerance test was done. The body weight and adiposity of these offspring were not different between the two groups. The HF offspring had glucose intolerance and impaired glucose-induced insulin response, mainly at the acute phase, observed since 6 weeks. The IpITT was not different between groups. At 14 weeks, fat was harvested from the two groups of offspring.

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Sex-Dependent Obesity Reduction from PPARa Activation by PDE9 Inhibition

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