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Phosphodiesterase‐4 inhibition as a therapeutic strategy for metabolic disorders
Author(s) -
Wu C.,
Rajagopalan S.
Publication year - 2016
Publication title -
obesity reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.845
H-Index - 162
eISSN - 1467-789X
pISSN - 1467-7881
DOI - 10.1111/obr.12385
Subject(s) - phosphodiesterase , lipolysis , allosteric regulation , cyclic adenosine monophosphate , steatohepatitis , endocrinology , second messenger system , medicine , biology , chemistry , microbiology and biotechnology , signal transduction , enzyme , biochemistry , adipose tissue , fatty liver , disease , receptor
Summary 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. © 2016 World Obesity