Phosphodiesterase-4 inhibition as a therapeutic strategy for metabolic disorders.

Phosphodiesterase-4 (PDE4) hydrolyses cyclic adenosine monophosphate (cAMP), a crucial secondary messenger for cellular adaptation to diverse external stimuli. The activity of PDE4 is tightly controlled by post-translational regulation, structure-based auto-regulation and locus specific 'compartmentalization' of PDE4 with its interactive proteins (signalsomes). Through these mechanisms, PDE4 regulates cAMP levels and shapes the cAMP signalling, directing signals from the diverse external stimuli to distinct microenvironments exquisitely. Derangement of the PDE4-cAMP signalling represents a pathophysiologically relevant pathway in metabolic disorders as demonstrated through a critical role in the processes including inflammation, disordered glucose and lipid metabolism, hepatic steatosis, abnormal lipolysis, suppressed thermogenic function and deranged neuroendocrine functions. A limited number of PDE4 inhibitors are currently undergoing clinical evaluation for treating disorders such as type 2 diabetes and non-alcoholic steatohepatitis. The discovery of novel PDE4 allosteric inhibitors and signalsome-based strategies targeting individual PDE4 variants may allow PDE4 isoform selective inhibition, which may offer safer strategies for chronic treatment of metabolic disorders.