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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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 8

PDE9-I does not impact body weight, fat, or PPARα downstream signaling in OVX DIO/mTAC mice.

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PDE9-I does not impact body weight, fat, or PPARα downstream signaling i...
(A) Total body weight, fat, and lean mass in non-OVX obese/CMS female mice before and after 8 weeks of treatment with either placebo or PDE9-I. n = 15/group; 2-way ANOVA, P value for interaction of treatment × time shown at lower right; paired Sidak’s multiple comparison test also displayed. (B) BAT histology shows enlarged adipocytes and reduced mitochondria density in the placebo group, which was not changed with PDE9-I (repeated 3 times). Scale bars: 100 μm. (C) Ppara mRNA expression increases in non-OVX to levels similar to those for male and OVX mice (n = 5 or 6/group). P value by Mann-Whitney test. (D) qPCR results for fatty acid metabolism and mitochondrial respiration genes in BAT from non-OVX model (log-transformed, 2-step Benjamini-Krieger-Yekutieli multiple comparison Mann-Whitney test; *q = 0.03, †q = 0.04, all others q > 0.5). (E) Metabolomics of acylcarnitines in BAT from normal controls and obese/CMS non-OVX with placebo vs. PDE9-I (n = 5/group, 2-step Benjamini-Krieger-Yekutieli multiple comparison Mann-Whitney test; for placebo vs. PDE9-I all q values > 0.5; for control chow (nonobese) versus placebo, all but one P ≤ 0.001 (C22, P = 0.006). (F) Venn diagram of ChIP-Seq–identified PPARα binding sites in HepG2 cells with PPARα stimulation alone or combined with ERα or ERβ costimulation. (G) KEGG pathway analysis from ChIP-Seq–identified genes with PPARα binding shows loss of fat metabolism–related pathways by coactivation with ERα or ERβ.