@article{9f5124fb83204c1dbfd65b935b2e9531,
title = "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.",
author = "Sumita Mishra and Nandhini Sadagopan and Brittany Dunkerly-Eyring and Susana Rodriguez and Sarver, {Dylan C.} and Ceddia, {Ryan P.} and Murphy, {Sean A.} and Hildur Knutsdottir and Jani, {Vivek P.} and Deepthi Ashok and Oeing, {Christian U.} and Brian O{\textquoteright}Rourke and Gangoiti, {Jon A.} and Sears, {Dorothy D.} and Wong, {G. William} and Sheila Collins and Kass, {David A.}",
note = "Funding Information: The authors thank the Johns Hopkins University School of Medicine (JHUSOM) Rodent Metabolism Core at the Center for Metabolism and Obesity Research for indirect calorimetry and glucose tolerance tests, the Phenotyping Core for MRI body composition analysis, the Small Animal CV Phenotyping and Models Core for echocardiography imaging and analysis and pressure-overload surgery, the JHU Imaging Core for electron microscopy slide preparation, and the JHU Deep Sequencing and Microarray Core Facility for sequencing. The study was supported by NIH grants R35-HL135827, RO1-HL-119012, P01HL10715, and AHA 16SFRN28620000 (to DAK); DK084171 (to GWW); RO1-HL134821 (to BOR); and DK116625 (to SC) and by AHA grants 16SFRN28620000 (to SC) and 16SFRN28420002 (to DDS) NIH grant F32 DK-116520 (to RPC), and OE 688/1-1 (Deutsche Forschungsgemeinschaft, to CUO). PF-04447943 was provided by Pfizer Inc. under a material transfer agreement. Publisher Copyright: {\textcopyright} 2021, American Society for Clinical Investigation.",
year = "2021",
month = nov,
doi = "10.1172/JCI148798",
language = "English (US)",
volume = "131",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "21",
}