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Published on: May 24, 2018
Inhibition of phosphodiesterase type 9 reduces obesity and cardiometabolic syndrome in mice
Sumita Mishra1, Nandhini Sadagopan1, Brittany Dunkerly-Eyring1
1Division of Cardiology, Department of Medicine, and.
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.
Insights
Phosphodiesterase 9A inhibition effectively treats obesity and metabolic dysfunction in male and ovariectomized female mice. This therapy reduces fat accumulation and enhances mitochondrial function, offering potential for human metabolic disease treatment.
Area of Science:
- Metabolic disease research
- Pharmacology
- Obesity and cardiometabolic syndrome
Background:
- Central obesity and cardiometabolic syndrome (CMS) pose significant global health challenges, necessitating novel therapeutic strategies.
- Existing treatments for obesity and CMS often have limitations, highlighting the need for innovative approaches.
Purpose of the Study:
- To investigate the efficacy of cyclic GMP-selective phosphodiesterase 9A inhibition (PDE9-I) as a potential therapy for diet-induced obesity and CMS.
- To explore the underlying mechanisms of PDE9-I, including its effects on fat metabolism, mitochondrial activity, and potential sexual dimorphism.
Main Methods:
- Utilized diet-induced obesity mouse models (male and ovariectomized/non-ovariectomized female mice) with or without cardiac pressure load.
- Administered PDE9-I and assessed effects on body composition, fat distribution, mitochondrial function, and cardiometabolic parameters.
- Investigated the role of PPARα (peroxisome proliferator-activated receptor alpha) and estrogen receptor-α in mediating PDE9-I effects.
Main Results:
- PDE9-I significantly reduced obesity, hepatic, and myocardial fat, and improved CMS markers in male and ovariectomized female mice.
- Inhibition of PDE9A stimulated mitochondrial activity in brown and white adipose tissue and enhanced lipolysis and mitochondrial respiration in adipocytes and myocytes.
- PPARα upregulation was essential for the observed therapeutic effects, which were diminished in non-ovariectomized females due to estrogen receptor-α interference.
Conclusions:
- PDE9-I demonstrates significant therapeutic potential for treating obesity and cardiometabolic syndrome, particularly in males and postmenopausal females.
- The findings highlight a crucial role for PPARα activation and reveal a significant sexual dimorphism in response to PDE9-I, influenced by estrogen.
- PDE9-I's established use in human trials for heart failure suggests potential for broader therapeutic applications in metabolic diseases.
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