Journal Article

Beyond Cyclic Nucleotides: Emerging Roles of Phosphodiesterases in Metabolic Disorders

Klinger, Francesca Gioia, Bertani, Nicole, Isidori, Andrea M., Sciarra, Francesca, Venneri, Mary Anna, D’Addato, Giorgia, Campolo, Federica, Assenza, Maria Rita

2025

Overview

Phosphodiesterases (PDEs) are a huge superfamily of enzymes that fine-tune the intracellular levels of cyclic nucleotides —cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP)—thus playing a pivotal role in the control of many cellular processes. While traditionally studied in the context of cardiovascular and neurological systems, mounting evidences highlight a crucial involvement of PDEs in metabolic homeostasis. This review explores the expanding landscape of PDEs function beyond classical cyclic nucleotide degradation, focusing on their roles in glucose and lipid metabolism and their implications in metabolic disorders, including obesity, type 2 diabetes (T2DM), and metabolic syndrome (MetS). Starting from an overview of the PDE superfamily, this work deeply examines the compartmentalized actions of cAMP-dependent protein kinase A (PKA) and cGMP-dependent protein kinase G (PKG) signaling pathways in key metabolically active tissues integrating PDE activities across different organs and disease states to offer a holistic view of their metabolic relevance. Special attention is given to the therapeutic relevance of PDE inhibitors (PDEi), distinguishing between established applications and emerging strategies targeting specific PDE isoforms in metabolic disease contexts to underscore the evolving concept that PDEs act as dynamic regulators of metabolic signaling networks. Understanding their isoform-specific and tissue-specific actions could thus open new avenues for therapeutic intervention in complex metabolic disorders.

• Publisher: IMR Press
• Subject: Adenosine triphosphate / Animals / Cyclic AMP / Cyclic AMP - metabolism / Cyclic AMP-Dependent Protein Kinases - metabolism / Cyclic GMP / Cyclic GMP - metabolism / Cyclic GMP-Dependent Protein Kinases - metabolism / cyclic nucleotide phosphodiesterases / Cyclic nucleotides / diabetes mellitus / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Type 2 - drug therapy / Diabetes Mellitus, Type 2 - enzymology / Diabetes Mellitus, Type 2 - metabolism / Glucose - metabolism / Homeostasis / Humans / Insulin resistance / Intracellular levels / Isoforms / Kinases / Lipid Metabolism / Metabolic Diseases - drug therapy / Metabolic Diseases - enzymology / Metabolic Diseases - metabolism / Metabolic disorders / Metabolic syndrome / Metabolic Syndrome - enzymology / Metabolic Syndrome - metabolism / Nucleotides / Nucleotides, Cyclic - metabolism / obesity / Obesity - enzymology / Obesity - metabolism / phosphodiesterase inhibitors / Phosphodiesterase Inhibitors - pharmacology / Phosphodiesterase Inhibitors - therapeutic use / Phosphoric Diester Hydrolases - metabolism / Protein kinase A / Protein kinase G / Signal Transduction