Inhibition of phosphodiesterase type 9 reduces obesity and cardiometabolic syndrome in mice
Sumita Mishra, … , Sheila Collins, David A. Kass
Sumita Mishra, … , Sheila Collins, David A. Kass
Published October 7, 2021
Citation Information: J Clin Invest. 2021;131(21):e148798. https://doi.org/10.1172/JCI148798.
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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 7

PDE9-I reduces obesity and fat mass and improves hepatic steatosis in OVX and male mice with DIO without superimposed pressure overload (mTAC).

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PDE9-I reduces obesity and fat mass and improves hepatic steatosis in OV...
(A) Body weight before and after 6 weeks of treatment with vehicle or PF-7493 (PDE9-I) in DIO OVX (n = 10) and male (n = 9) mice. P value in lower right is for interaction of drug treatment and time-change, by 2-way ANOVA. P values above are from Sidak’s multiple comparison test. Baseline values for each group were essentially identical. (B) Fat mass for iWAT and gWAT in both OVX and male DIO mice from same study. P values from Kruskal-Wallis test. (C) Example liver histology and summary data (n = 10/group). There was substantial steatosis reflected by increased hepatic mass and increased percentage area occupied by large lipid vacuoles. P values by Kruskal-Wallis test. (D) Expression of PPARα-associated FA regulatory genes normalized to Gapdh in BAT from DIO OVX mice (n = 7 or 8). Two-step Benjamini-Krieger-Yekutieli multiple comparison Kruskal-Wallis q values shown. (E) Expression of Nppa/Gapdh in normal diet control versus DIO with vehicle or PDE9-I. P values from Kruskal-Wallis with Dunn’s multiple comparison test.