ArticleThe Journal of clinical investigation2021
Inhibition of phosphodiesterase type 9 reduces obesity and cardiometabolic syndrome in mice.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
26 citing papers in PubMed, 41 citations in OpenAlex.
- Serum proteins associated with LDL-C and non-HDL-C reduction in response to dietary interventions in the DASH and DASH-Sodium trials.Food & function · 2025Trial
- Sex-Specific Associations Between Per- and Polyfluoroalkyl Substances and the Risk of Type 2 Diabetes: The Role of Genetic Susceptibility and Lipid Metabolism.Environmental health perspectives · 2026Article
- Review
- Transcriptomic profiling and machine learning uncover gene signatures of psoriasis endotypes and disease severity.Communications medicine · 2026Article
- The Adipokine Hypothesis of Heart Failure With a Preserved Ejection Fraction: A Novel Framework to Explain Pathogenesis and Guide Treatment.Journal of the American College of Cardiology · 2025Review
- Effect of cholesterol on distribution, cell uptake, and protein corona of lipid microspheres at sites of cardiovascular inflammatory injury.Journal of pharmaceutical analysis · 2025Article
- FNDC4 Prevents Aging-Related Cardiac Dysfunction: By Restoring AMPKα/PPARα-Dependent Mitochondrial Function.JACC. Basic to translational science · 2025Article
- Cyclic nucleotide phosphodiesterases as drug targets.Pharmacological reviews · 2025Review
- E3 ubiquitin ligase CHIP facilitates cAMP and cGMP signalling cross-talk by polyubiquitinating PDE9A.The EMBO journal · 2025Article
- Cardiac cGMP Regulation and Therapeutic Applications.Hypertension (Dallas, Tex. : 1979) · 2025Review
- Phosphodiesterases: Evolving Concepts and Implications for Human Therapeutics.Annual review of pharmacology and toxicology · 2025Review
- PDE9A Inhibition Improves Coronary Microvascular Rarefaction and Left Ventricular Diastolic Dysfunction in the ZSF1 Rat Model of HFpEF.Microcirculation (New York, N.Y. : 1994) · 2024Article
- SGLT2 inhibitors protect against diabetic cardiomyopathy and atrial fibrillation through a CaMKII independent mechanism.bioRxiv : the preprint server for biology · 2024Article
- Carvedilol Activates a Myofilament Signaling Circuitry to Restore Cardiac Contractility in Heart Failure.JACC. Basic to translational science · 2024Article
- Association of natriuretic peptides and receptor activity with cardio-metabolic health at middle age.Scientific reports · 2024Article
- Transcriptional determinants of lipid mobilization in human adipocytes.Science advances · 2024Article
- Disrupted propionate metabolism evokes transcriptional changes in the heart by increasing histone acetylation and propionylation.Nature cardiovascular research · 2023Article
- Dysregulated Cyclic Nucleotide Metabolism in Alcohol-Associated Steatohepatitis: Implications for Novel Targeted Therapies.Biology · 2023Article
- An improved reporter identifies ruxolitinib as a potent and cardioprotective CaMKII inhibitor.Science translational medicine · 2023Article
- Pharmacologic blockade of the natriuretic peptide clearance receptor promotes weight loss and enhances insulin sensitivity in type 2 diabetes.Translational research : the journal of laboratory and clinical medicine · 2023Article
Corrections and comments
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Authors and funding
17 authors at 4 institutions in 1 country.
Funding
Abstract
Central obesity with cardiometabolic syndrome (CMS) is a major global contributor to human disease, and effective therapies are needed. Here, we show that cyclic GMP-selective phosphodiesterase 9A inhibition (PDE9-I) in both male and ovariectomized female mice suppresses preestablished severe diet-induced obesity/CMS with or without superimposed mild cardiac pressure load. PDE9-I reduces total body, inguinal, hepatic, and myocardial fat; stimulates mitochondrial activity in brown and white fat; and improves CMS, without significantly altering activity or food intake. PDE9 localized at mitochondria, and its inhibition in vitro stimulated lipolysis in a PPARα-dependent manner and increased mitochondrial respiration in both adipocytes and myocytes. PPARα upregulation was required to achieve the lipolytic, antiobesity, and metabolic effects of PDE9-I. All these PDE9-I-induced changes were not observed in obese/CMS nonovariectomized females, indicating a strong sexual dimorphism. We found that PPARα chromatin binding was reoriented away from fat metabolism-regulating genes when stimulated in the presence of coactivated estrogen receptor-α, and this may underlie 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.