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Publication
Increased Energy Expenditure and Protection From Diet-Induced Obesity in Mice
Lacking the cGMP-Specific Phosphodiesterase PDE9.
Authors Ceddia RP, Liu D, Shi F, Crowder MK, Mishra S, Kass DA, Collins S
Submitted By Submitted Externally on 1/10/2022
Status Published
Journal Diabetes
Year 2021
Date Published 12/1/2021
Volume : Pages 70 : 2823 - 2836
PubMed Reference 34620617
Abstract Cyclic nucleotides cAMP and cGMP are important second messengers for the
regulation of adaptive thermogenesis. Their levels are controlled not only by
their synthesis, but also their degradation. Since pharmacological inhibitors of
cGMP-specific phosphodiesterase 9 (PDE9) can increase cGMP-dependent protein
kinase signaling and uncoupling protein 1 expression in adipocytes, we sought to
elucidate the role of PDE9 on energy balance and glucose homeostasis in vivo.
Mice with targeted disruption of the PDE9 gene, Pde9a, were fed nutrient-matched
high-fat (HFD) or low-fat diets. Pde9a-/- mice were resistant to HFD-induced
obesity, exhibiting a global increase in energy expenditure, while brown adipose
tissue (AT) had increased respiratory capacity and elevated expression of Ucp1
and other thermogenic genes. Reduced adiposity of HFD-fed Pde9a-/- mice was
associated with improvements in glucose handling and hepatic steatosis. Cold
exposure or treatment with ß-adrenergic receptor agonists markedly decreased
Pde9a expression in brown AT and cultured brown adipocytes, while Pde9a-/- mice
exhibited a greater increase in AT browning, together suggesting that the
PDE9-cGMP pathway augments classical cold-induced ß-adrenergic/cAMP AT browning
and energy expenditure. These findings suggest PDE9 is a previously unrecognized
regulator of energy metabolism and that its inhibition may be a valuable avenue
to explore for combating metabolic disease.




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