Peripherally administered desacetyl α-MSH and α-MSH both influence postnatal rat growth and associated rat hypothalamic protein expression

Abstract

. 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 ...

Neonatal melanocortin receptor agonist treatment reduces play fighting and promotes adult attachment in prairie voles in a sex-dependent manner

“…PF446687 treated neonates did not weigh less than vehicle controls, but displayed slowed weight gain (Figure 6A). Although the MC4R system is critically involved in feeding, MC agonists do not always lead to weight loss (Wu et al, 2006; Muceniece et al, 2007). Additionally, multiple second messenger pathways activated from the same receptor or from different MCR4 agonists (Konda et al, 1994; Nickolls et al, 2005) or additional activation of the MC3R (Chen et al, 2000) may account for this discrepancy.…”

“…Melanocortins promote neuroplasticity and neurotrophin activity (Joosten et al, 1996; Xu et al, 2003; Shen et al, 2013), which may lead to persistent changes in neural architecture into adulthood. Indeed, alpha-MSH treatment for the first two weeks of life alters hypothalamic expression of cytoskeletal proteins involved in synaptic plasticity (Wu et al, 2006). MC4R stimulation also induces hypothalamic brain derived neurotropic factor release, which exerts effects on feeding and cardiovascular function, but may also position the system to regulate synaptic plasticity (Nicholson et al, 2007; Gomez-Pinilla et al, 2008).…”

“…Interestingly, neonatal administration of α-MSH and ACTH-like peptides to rats leads to enhancements in adult attention to relevant stimuli (Champney et al, 1976), learning (Beckwith et al, 1977b; Acker et al, 1985), social contact in an open field (Beckwith et al, 1977a), and reductions in adult anxiety (Felszeghy et al, 1993). Early α-MSH treatment also impacts hypothalamic cytoskeletal proteins (Wu et al, 2006), hypothalamic dopamine neuron development (Egles et al, 1998), and neurite outgrowth (Joosten et al, 1996), thus leading to functional and structural changes in neural development. As MC agonists impact a variety of neural systems involved in sociality and acute MC4R stimulation promotes adult pair bonding, early MC stimulation may also stimulate encoding of early social information and lead to long-term organizational changes in social behavior.…”

Adenylate Kinase and AMP Signaling Networks: Metabolic Monitoring, Signal Communication and Body Energy Sensing

“…Other studies indicate that adenylate kinase isoforms in the brain may contribute to neuronal maturation and regeneration [ 23 , 224 ]. Activation of melanocortin system, which is involved in regulation of appetite, metabolism and body weight, increases expression of adenylate kinase AK1 in the hypothalamus [ 225 ]. AMPK, a master metabolic sensor present in hypothalamus, responds to adenylate kinase integrated AMP levels, and plays a critical role in hormonal and nutrient-derived anorexigenic and orexigenic signaling [ 62 , 72 , 226 ].…”

Prolylcarboxypeptidase in Cardiovascular Physiology and Pathophysiology

“…Understanding this process can provide insight into how PRCP functions in human cerebrospinal fluid. α-MSH appears to be a multifunctional neurohormone [11], which regulates a variety of physiological processes including energy balance regulation through centrally pathway and lipolysis in adipocytes [12]. PRCP metabolizes the anorexigenic α-MSH, leading to an activation of an orexigenic pathway.…”