Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 131, Issue 21, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI148798
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Funding
- NIH [R35-HL135827, RO1-HL-119012, P01HL10715, F32 DK-116520]
- AHA [16SFRN28620000, DK084171, RO1-HL134821, DK116625]
- Deutsche Forschungsgemeinschaft [OE 688/1-1]
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Inhibition of PDE9 shows promising effects in improving obesity and cardiometabolic syndrome symptoms, especially in male and ovariectomized female mice. PDE9-I stimulates mitochondrial activity in brown and white fat, reduces various fat deposits, and improves CMS without significantly affecting activity or food intake.
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 PPAR alpha-dependent manner and increased mitochondrial respiration in both adipocytes and myocytes. PPAR alpha 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 PPAR alpha chromatin binding was reoriented away from fat metabolism-regulating genes when stimulated in the presence of coactivated estrogen receptor-alpha, 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.
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