Sex-Dependent Obesity Reduction from PPARa Activation by PDE9 Inhibition
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ABSTRACT:
PROVIDER: PRJNA659651 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12532151_1.fastq.gz | Fastqsanger.gz | |||
| SRR12532151_2.fastq.gz | Fastqsanger.gz | |||
| SRR12532152_1.fastq.gz | Fastqsanger.gz | |||
| SRR12532152_2.fastq.gz | Fastqsanger.gz | |||
| SRR12532153_1.fastq.gz | Fastqsanger.gz |
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Project description: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.
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Project description:Inhibition of adipocyte triglyceride lipase (ATGL/PNPLA2) activity in insulin resistance and non-alcoholic fatty liver disease is an attractive therapeutic target. This study evaluated the impact of Atglistatin-mediated ATGL inhibition on non-alcoholic steatohepatitis (NASH) development in diabetic and hyperlipidaemic mice. Streptozotocin-injected male mice were fed an HFD to induce NASH. We analysed liver histology, hepatic lipid content, immunohistochemistry, RNA sequencing, and serum biochemistry. Mechanistically, we treated Caco2 cells, human primary ileum-derived organoids, and HepG2 ATGL KD cells with the novel human ATGL inhibitor NG-497 and WY14643. Atglistatin reduced body and liver weights, total liver lipid content, and improved blood sugar levels consistent with improved liver enzymes, histological liver injury, and NAFLD activity scores. Mechanistically, Atglistatin reduced Cpt1a and Abca1, suggesting impaired Ppara signalling that favours hydrophilic bile acids (BA) synthesis since Cyp7a1, Cyp27a1, and Cyp2c70 were increased while Cyp8b1 was reduced. Accordingly, Intestinal lipid transporters, Abca1 and Cd36, were reduced, consistent with the reduction of liver TAG species, mostly linoleic acids. We used human-specific ATGL inhibitor NG-497 to validate the mouse findings. The NG-497-treated human primary ileum organoids and Caco2 cells showed reduced ATGL, ABCA1, FATP5, CD36, and MTTP. PPARa signalling was impaired in the ileum organoids and HepG2 treated with NG-497 and in HepG2 ATGL KD since PPARa, CPT1a, AOX, ABCA1, and CYP8B1 were reduced, and CYP7A1 increased. Inhibition of ATGL activity reduces the availability of ligands for Ppara activation leading to impaired Ppara signalling, which translate into hydrophilic BA that interferes with dietary lipid absorption, improving metabolic disturbances. The validation with the NG-497 should open a new clinical avenue for NAFLD clinical trial and treatment.
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Project description:Obesity is a global rising problem with epidemiological dimension. Obese parents can have programming effects on their offspring leading to obesity and associated diseases in later life. This constitutes a vicious circle. Epidemiological data and studies in rodents demonstrated differential programming effects in male and female offspring, but the timing of their developmental origin is not known. This study investigated if sex-specific programming effects of parental obesity can already be detected in the pre-implantation period. Diet induced obese male or female mice were mated with normal-weight partners and blastocysts were recovered. Gene expression profiling revealed sex-specific responses of the blastocyst transcriptome to maternal and paternal obesity. The changes in the transcriptome of male blastocysts were more pronounced than those of female blastocysts, with a stronger impact of paternal than of maternal obesity. The sperm of obese mice revealed an increased abundance of several miRNAs compared to lean mice. Our study indicates that sex-specific programming effects of parental obesity already start in the pre‑implantation period and reveals specific alterations of the sperm miRNA profile as mechanistic link to programming effects of paternal obesity. We used microarrays to analyze the transcriptomes of sex-sorted blastocysts of mice, with one parent (either mother or father) being obese at the time of conception and compared it to the transcriptome of blasocysts of peri-conceptionally lean parents.
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