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

J Clin Invest. 2021 Nov 1;131(21):e148798. doi: 10.1172/JCI148798.


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.

Keywords: Fatty acid oxidation; Metabolism; Obesity; Phosphodiesterases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / genetics
  • 3',5'-Cyclic-AMP Phosphodiesterases / metabolism*
  • Adipose Tissue / embryology*
  • Animals
  • Female
  • Male
  • Metabolic Syndrome / enzymology*
  • Metabolic Syndrome / genetics
  • Mice
  • Mice, Transgenic
  • Mitochondria / enzymology
  • Mitochondria / genetics
  • Obesity / enzymology*
  • Obesity / genetics
  • PPAR alpha / genetics
  • PPAR alpha / metabolism


  • PPAR alpha
  • Ppara protein, mouse
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Pde9a protein, mouse