Natriuretic Peptide Signaling Contributes to the Adipose Tissue Thermogenic Program in Response to Cold Exposure

The sympathetic nerve derived norepinephrine acts via the β-adrenergic receptor (βAR) signaling cascade to drive the adipose tissue thermogenic gene program in response to cold exposure. In parallel, the cardiac derived natriuretic peptides (NPs) can also stimulate adipocyte thermogenesis through the NP receptor A (NPRA) signaling pathway. The role and mechanism for βAR signaling in adipocyte thermogenesis has been well described, while the in vivo physiological function for NP signaling in this process is not fully understood. Here we show that in adipose tissues the expression of Npr3, encoding the clearance NP receptor C (NPRC), is suppressed by cold exposure or by treatment with the β ₃AR agonist CL-316,243. The down-regulation of Npr3 gene expression depends on the action of the cAMP response element-binding (CREB) protein, a downstream effector of the βAR signaling cascade. Deletion of NPRC in adipocytes enhances NP signaling and further increases the adipose thermogenic gene expression after cold exposure. Inactivation of the sympathetic nerve inputs by surgical denervation leads to an impaired thermogenic response in the brown adipose tissue (BAT). However, the thermogenic defects following BAT denervation can be restored by enhancing NP signaling via adipocyte-specific NPRC deletion. Our data reveals a crosstalk mechanism where sympathetic stimulation of βAR signaling potentiates the adipose NP signaling pathway by down-regulation of NPRC during cold exposure, suggesting the NP signaling network is a crucial component of the adipose tissue thermogenic program in response to cold stress.