title: Mechanisms by which the orexigen NPY regulates anorexigenic α-MSH and TRH.
abstract: Protein posttranslational processing is a cellular mechanism fundamental to the generation of bioactive peptides, including the anorectic α-melanocyte-stimulating hormone (α-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 α-MSH and TRH. The mechanism by which NPY regulates α-MSH output, however, is not well understood. Our results reveal that NPY inhibited the posttranslational processing of α-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 α-MSH-induced increase in TRH production by two mechanisms. First, NPY decreased α-MSH-induced CREB phosphorylation, which normally enhances TRH transcription. Second, NPY decreased the amount of α-MSH in the PVN. Collectively, these results underscore the significance of the interaction between NPY and α-MSH in the central regulation of energy balance and indicate that posttranslational processing is a mechanism that plays a specific role in this interaction.
authors: Division of Endocrinology, Department of Medicine, The Warren Alpert Medical School of Brown University/Rhode Island Hospital, Providence, RI 02903, USA.
authors: Nicole E
authors: NE
authors: Cyr
authors: Anika M
authors: AM
authors: Toorie
authors: Jennifer S
authors: JS
authors: Steger
authors: Matthew M
authors: MM
authors: Sochat
authors: Samantha
authors: S
authors: Hyner
authors: Mario
authors: M
authors: Perello
authors: Ronald
authors: R
authors: Stuart
authors: Eduardo A
authors: EA
authors: Nillni
mesh_terms: D000818:Animals; D001069:Appetite Regulation; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D057967:Infusions, Intraventricular; D008297:Male; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D009478:Neuropeptide Y / Q000008:administration & dosage / Q000378:metabolism*; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism*; D010766:Phosphorylation; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D045706:Proprotein Convertase 2 / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D051381:Rats; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000378:metabolism; D013973:Thyrotropin-Releasing Hormone / Q000378:metabolism*; D000521:alpha-MSH / Q000378:metabolism*
chemical_list: C508137:Creb1 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor; D000521:alpha-MSH; D013973:Thyrotropin-Releasing Hormone; D011333:Pro-Opiomelanocortin; D045706:Proprotein Convertase 2