Natriuretic Peptide Signaling – Some Old, Some New – and Roles in Adipose Biology

The natriuretic peptides (NPs) signal through their membrane receptors NPRA (GC-A; for ANP and BNP) and NPRB (GC-B; for CNP), which generate cGMP. A third receptor, NPRC, is a negative regulator of NP signaling: it binds all three NPs and internalizes/degrades them. The relative levels of NPRA or NPRB to NPRC thus dictates the signaling strength of cGMP produced. In recent studies we explored the possibility that another means by which NPRC might dampen signaling through NPRA and NPRB is through the formation of receptor heterodimers. The consequence of such an event would similarly be a decrease in cGMP production. We show evidence that such heterodimers do form and that the blunting of cGMP signaling may also include the internalization of these heterodimers. Other events that seem to contribute to the net signaling strength of NPs is a regulated decrease in 'inhibitory' components of the NP signaling system. In these studies, we have focused on adipose tissue, an important 'organ' that is a pivotal regulator of whole-body metabolic homeostasis. ANP and BNP stimulate adipocyte lipolysis as well as a process of net energy expenditure in brown and 'beige' adipocytes. We show that two important 'negative' regulators of NP signaling in adipocytes – NPRC and phosphodiesterase-9 (PDE9) – are transcriptionally down-regulated during catecholamine/β-adrenergic receptor stimulation of lipolysis and brown/beige adipocyte thermogenesis. In concert with elevated ANP production and release from the heart, these events appear to coordinately foster NP signaling strength in the adipocyte to protect from fat mass gain and metabolic disease.