Key result
Inhibition of PDE-5A and NEP in human adipocytes did not modify baseline or ANP-mediated lipolysis, indicating these enzymes do not play a major role in regulating this process.
Functional PDE-5A and NEP activities are present in human adipocytes but do not play a major role in regulating ANP-mediated lipolysis.
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PDE-5A/NEP inhibition unlikely to alter lipolysis in human adipocytes; leaves open their roles in other metabolic pathways.
BACKGROUND AND PURPOSE: Atrial natriuretic peptide (ANP) stimulates lipolysis in human adipocyte through a cGMP signalling pathway, the regulation of which is poorly known. Since phosphodiesterases (PDE) and neutral endopeptidase (NEP) play a major role in the regulation of the biological effects of natriuretic peptides in the cardiovascular and renal systems, we investigated whether these mechanisms could regulate cGMP signalling and ANP-mediated lipolysis in human adipocytes. EXPERIMENTAL APPROACH: The presence of cGMP-specific PDE and NEP in differentiated pre-adipocytes and in mature adipocytes was evaluated by real-time qPCR and Western blot. The effect of non-selective and selective inhibition of these enzymes on ANP-mediated cGMP signalling and lipolysis was determined in isolated mature adipocytes. KEY RESULTS: PDE-5A was expressed in both pre-adipocytes and adipocytes. PDE-5A mRNA and protein levels decreased as pre-adipocytes differentiated (10 days). PDE-5A is rapidly activated in response to ANP stimulation and lowers intracellular cGMP levels. Its selective inhibition by sildenafil partly prevented the decline in cGMP levels. However, no changes in baseline- and ANP-mediated lipolysis were observed under PDE-5 blockade using various inhibitors. In addition, NEP mRNA and protein levels gradually increased during the time-course of pre-adipocyte differentiation. Thiorphan, a selective NEP inhibitor, completely abolished NEP activity in human adipocyte membranes but did not modify ANP-mediated lipolysis. CONCLUSIONS AND IMPLICATIONS: Functional PDE-5A and NEP activities were present in human adipocytes, however these enzymes did not play a major role in the regulation of ANP-mediated lipolysis.
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Moro et al. (2007) studied this question. PDE-5A and NEP inhibitors (sildenafil, thiorphan) vs. No inhibition was evaluated on ANP-mediated lipolysis. Inhibition of PDE-5A and NEP in human adipocytes did not modify baseline or ANP-mediated lipolysis, indicating these enzymes do not play a major role in regulating this process.
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