. Peripherally administered desacetyl ␣-MSH and ␣-MSH both influence postnatal rat growth and associated rat hypothalamic protein expression. Am J Physiol Endocrinol Metab 291: E1372-E1380, 2006. First published July 25, 2006 doi:10.1152/ajpendo.00480.2005.-Desacetyl ␣-MSH predominates over ␣-MSH during development, but whether it is biologically active and has a physiological role is unclear. We compared the effects of 0.3␣-MSH on postnatal body growth by administering the peptides subcutaneously daily for postnatal days 0 -14 and also used a twodimensional gel electrophoresis gel-based proteomic approach to analyze protein changes in hypothalami, the relay center for body weight and growth regulation, after 14 days of treatment. We found that the growth rate between days 1 and 10 was significantly decreased by desacetyl ␣-MSH but not by ␣-MSH, but by day 14, a time reported for development of a mature pattern of hypothalamic innervation, both peptides had significantly increased neonatal growth compared with PBS-treated control rats. Desacetyl ␣-MSH significantly increased spleen weight, but ␣-MSH had no effect. ␣-MSH significantly decreased kidney weight, but desacetyl ␣-MSH had no effect. Both desacetyl ␣-MSH and ␣-MSH significantly decreased brain weight. By 14 days, both peptides significantly changed expression of a number of hypothalamic proteins, specifically metabolic enzymes, cytoskeleton, signaling, and stress response proteins. We show that peripherally administered desacetyl ␣-MSH is biologically active and induces responses that can differ from those for ␣-MSH. In conclusion, desacetyl ␣-MSH appears to be an important regulator of neonatal rat growth. melanocortin peptides; ␣-melanocyte-stimulating hormone; melanocortin receptors; proopiomelanocortin; hypothalamus THE PIVOTAL ROLE of the melanocortin system in regulation of apetite, metabolism, body size, and body weight is demonstrated clearly by the human melanocortin-4 receptor (MC4R) (24, 65) and proopiomelanocortin (POMC) (34) variants, three knockout mouse models (POMC, MC3R, and MC4R) (10,14,29,70), the spontaneously occurring dominant agouti mouse (68), and a mouse ectopically overexpressing agouti generelated peptide (26), all of which promote obesity. Still unresolved, though, are the roles of each POMC-derived peptide and the central melanocortin-signaling pathways.The melanocortin peptides ␣-melanocyte-stimulating hormone (␣-MSH) and desacetyl ␣-MSH are two endogenous peptides derived from a precursor protein, POMC, through posttranslational processing (46). NH 2 -terminal acetylation of desacetyl ␣-MSH to form ␣-MSH occurs in secretory vesicles just prior to exocytosis (42, 66), but not all desacetyl ␣-MSH is acetylated, since desacetyl ␣-MSH is present in the circulation and brain of rodents and humans. The major form of plasma immunoreactive MSH is ␣-MSH in rodents and desacetyl ␣-MSH in humans (22,40), and the relative abundance of these two MSH peptides is developmentally regulated (11,23). Desacetyl ␣-MSH predominates in rodent ...