Mechanisms by which the orexigen NPY regulates anorexigenic α-MSH and TRH

Cyr NE, Toorie AM, Steger JS, Sochat MM, Hyner S, Perello M, Stuart R, Nillni EA. Mechanisms by which the orexigen NPY regulates anorexigenic alpha-MSH and TRH. Am J Physiol Endocrinol Metab 67: E640-E650, 2013. First published January 15, 2013; doi:10.1152/ajpendo.00448.2012.-Protein posttranslational processing is a cellular mechanism fundamental to the generation of bioactive peptides, including the anorectic alpha-melanocyte-stimulating hormone (alpha-MSH) and thyrotropin-releasing hormone (TRH) peptides produced in the hypothalamic arcuate (ARC) and paraventricular (PVN) nuclei, respectively. Neuropeptide Y (NPY) promotes positive energy balance in part by suppressing alpha-MSH and TRH. The mechanism by which NPY regulates alpha-MSH output, however, is not well understood. Our results reveal that NPY inhibited the posttranslational processing of alpha-MSH's inactive precursor proopiomelanocortin (POMC) by decreasing the prohormone convertase-2 (PC2). We also found that early growth response protein-1 (Egr-1) and NPY-Y1 receptors mediated the NPY-induced decrease in PC2. NPY given intra-PVN also decreased PC2 in PVN samples, suggesting a reduction in PC2-mediated pro-TRH processing. In addition, NPY attenuated the alpha-MSH-induced increase in TRH production by two mechanisms. First, NPY decreased alpha-MSH-induced CREB phosphorylation, which normally enhances TRH transcription. Second, NPY decreased the amount of alpha-MSH in the PVN. Collectively, these results underscore the significance of the interaction between NPY and alpha-MSH in the central regulation of energy balance and indicate that posttranslational processing is a mechanism that plays a specific role in this interaction.