Pde5a Deficiency Prevents Diet-Induced Obesity via Adipose cAMP-PKA Activation Enhancing Fat Browning

Federica Campolo; Ottavia Giampaoli; Federica Barbagallo; Biagio Palmisano; Anna Di Maio; Francesca Sciarra; Flavio Rizzo; Serena Monti; Sandra Albanese; Silvia Cardarelli; Maria Rita Assenza; Eleonora Poggiogalle; Adriano Patriarca; Fabio Sciubba; Antonio Filippini; Andrea Lenzi; Daniele Gianfrilli; Mauro Giorgi; Susanna Dolci; Fabio Naro; Maurilio Sampaolesi; Mara Riminucci; Miccheli Alfredo; Lino Tessarollo; Mary Anna Venneri; Andrea Maria Isidori

doi:10.1016/j.molmet.2025.102243

Cell BiologyMolecular MetabolismSep 3, 2025

Peer-reviewed journal article

Pde5a Deficiency Prevents Diet-Induced Obesity via Adipose cAMP-PKA Activation Enhancing Fat Browning

Federica Campolo iD, Ottavia Giampaoli iD, Federica Barbagallo iD, Biagio Palmisano iD, Anna Di Maio, Francesca Sciarra iD, Flavio Rizzo iD, Serena Monti iD, Sandra Albanese iD, Silvia Cardarelli iD, Maria Rita Assenza iD, Eleonora Poggiogalle iD, Adriano Patriarca iD, Fabio Sciubba iD, Antonio Filippini iD, Andrea Lenzi iD, Daniele Gianfrilli iD, Mauro Giorgi iD, Susanna Dolci iD, Fabio Naro iD, Maurilio Sampaolesi iD, Mara Riminucci iD, Miccheli Alfredo, Lino Tessarollo iD, Mary Anna Venneri iD, Andrea Maria Isidori iD

Abstract

Cyclic nucleotides are critical regulators of adaptive thermogenesis and adipogenesis, with their intracellular levels finely tuned by phosphodiesterases. Phosphodiesterase type 5 (PDE5A) modulates cyclic guanosine monophosphate levels in adipocytes. While PDE5A inhibition has shown promise in patients with diabetes, its role in metabolism remains unclear. Using Pde5a knockout mouse models, we demonstrated that mice lacking Pde5a exhibit enhanced browning of white adipose tissue and reduced hepatic fat content. Following high-fat diet, Pde5a-/- mice are resistant to obesity, displaying improved glucose metabolism and enhanced thermogenesis. These protective effects stem from an early developmental knockdown of Pde5a, leading to a metabolic reprogramming driven by cAMP-PKA pathway activation. The convergence of cGMP and cAMP signaling orchestrates thermogenic and systemic metabolic adaptations. Our findings establish PDE5A as a novel regulator of energy homeostasis, suggesting its inhibition as a valuable adjuvant therapy for metabolic disorders.

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