Inhibition of phosphodiesterase type 9 reduces obesity and cardiometabolic syndrome in mice
Sumita Mishra, Nandhini Sadagopan, Brittany Dunkerly-Eyring, Susana Rodriguez, Dylan C. Sarver, Ryan P. Ceddia, Sean A. Murphy, Hildur Knutsdottir, Vivek P. Jani, Deepthi Ashok, Christian U. Oeing, Brian O’Rourke, Jon A. Gangoiti, Dorothy D. Sears, G. William Wong, Sheila Collins, David A. Kass
Sumita Mishra, Nandhini Sadagopan, Brittany Dunkerly-Eyring, Susana Rodriguez, Dylan C. Sarver, Ryan P. Ceddia, Sean A. Murphy, Hildur Knutsdottir, Vivek P. Jani, Deepthi Ashok, Christian U. Oeing, Brian O’Rourke, Jon A. Gangoiti, Dorothy D. Sears, G. William Wong, Sheila Collins, David A. Kass
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Research Article Metabolism

Inhibition of phosphodiesterase type 9 reduces obesity and cardiometabolic syndrome in mice

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.

Authors

Sumita Mishra, Nandhini Sadagopan, Brittany Dunkerly-Eyring, Susana Rodriguez, Dylan C. Sarver, Ryan P. Ceddia, Sean A. Murphy, Hildur Knutsdottir, Vivek P. Jani, Deepthi Ashok, Christian U. Oeing, Brian O’Rourke, Jon A. Gangoiti, Dorothy D. Sears, G. William Wong, Sheila Collins, David A. Kass

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Figure 6

Inhibition of PPARα blocks beneficial effects of PDE9-I in OVX model.

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Inhibition of PPARα blocks beneficial effects of PDE9-I in OVX model. (A...
(A) Quantitative PCR of PPARα-associated genes in myocardial tissue from OVX obese/CMS mice treated with PDE9-I with and without PPARα-I. Mean ± SD, 2-step Benjamini-Krieger-Yekutieli multiple comparison Mann-Whitney, q values shown. *P ≤ 5 × 10–5; #P = 0.007. (B) Effect of PPARα coinhibition on PDE9-I–induced reductions in total body, fat, and lean mass, and increases in VO2 and CO2 in OVX obese/CMS mice. Results for placebo-treated OVX mice (derived from data in Figure 1) are plotted with median (dark line) and 75% to 25% confidence intervals (shaded). The addition of PPARα-I reversed PDE9-I–mediated responses in these parameters, returning their values to those with placebo for all by lean mass that rose by 5% (n = 10/group). P values displayed from Kruskal-Wallis (includes all 3 groups) with Dunn’s multiple comparison test. (C) iWAT and gWAT weight in OVX mice PDE9-I with and without PPARα-I versus placebo (n = 9/group). One-way ANOVA with Tukey’s multiple comparison test. (D) Percentage fractional shortening (FS) from the same experiment (n = 7, 5); 2-way ANOVA with Sidak’s multiple comparison test.