Differential effects of fasting and leptin on proopiomelanocortin peptides in the arcuate nucleus and in the nucleus of the solitary tract.
The alpha-melanocyte-stimulating hormone (alpha-MSH), derived from proopiomelanocortin (POMC), is generated by a posttranslational processing mechanism involving the prohormone convertases (PCs) PC1/3 and PC2. In the brain, alpha-MSH is produced in the arcuate nucleus (ARC) of the hypothalamus and in the nucleus of the solitary tract (NTS) of the medulla. This peptide is key in controlling energy balance, as judged by changes observed at transcriptional level. However, little information is available regarding the biosynthesis of the precursor POMC and the production of its processed peptides during feeding, fasting, and fasting plus leptin in the ARC compared with the NTS in conjunction with the PC activity. In this study we found that, in the ARC, pomc mRNA, POMC-derived peptides, and PC1/3 all decreased during fasting, and administration of leptin reversed these effects. In contrast, in the NTS, where there is a large amount of a 28.1-kDa peptide similar in size to POMC, the 28.1-kDa peptide and other POMC-derived peptides, including alpha-MSH, were further accumulated in fasting conditions, whereas pomc mRNA decreased. These changes were not reversed by leptin. We also observed that, during fasting, PC2 levels decreased in the NTS. These data suggest that, in the NTS, fasting induced changes in POMC biosynthesis, and processing is independent of leptin. These observations indicate that changes in energy status affect POMC in the brain in a tissue-specific manner. This represents a novel aspect in the regulation of energy balance and may have implications in the pathophysiology of obesity.
Perello
Mario
M
Division of Endocrinology, Department of Medicine, Brown University, Rhode Island Hospital, Providence, Rhode Island 02903, USA.
Stuart
Ronald C
RC
Nillni
Eduardo A
EA
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D053497:Corticotropin-Like Intermediate Lobe Peptide / Q000378:metabolism; D004734:Energy Metabolism; D005215:Fasting / Q000378:metabolism*; D007150:Immunohistochemistry; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D011333:Pro-Opiomelanocortin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D043484:Proprotein Convertases / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017552:Solitary Nucleus / Q000187:drug effects / Q000378:metabolism*; D000521:alpha-MSH / Q000378:metabolism
D020738:Leptin; D012333:RNA, Messenger; D011994:Recombinant Proteins; D053497:Corticotropin-Like Intermediate Lobe Peptide; D000521:alpha-MSH; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D043484:Proprotein Convertases