Endocrinology, doi:10.1210/en.2006-1686
Endocrinology Vol. 148, No. 9 4201-4207
Copyright © 2007 by The Endocrine Society
Neuropeptide Processing and Its Impact on Melanocortin Pathways
Lynn E. Pritchard and
Anne White
Endocrine Sciences, Faculties of Life Sciences and Medical and Human Sciences, University of Manchester, Manchester M13 9NT, United Kingdom
Address all correspondence and requests for reprints to: Professor Anne White, Endocrine Sciences Research Group, CTF Building, 46 Grafton Street, Manchester M13 9NT, United Kingdom. E-mail: anne.white{at}manchester.ac.uk.
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Abstract
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Proopiomelanocortin (POMC) is processed in an intracellular secretory pathway, primarily to enable release of ACTH from the pituitary and 
-MSH from hypothalamic neurons and skin. However, processing is incomplete and unprocessed POMC is secreted from all three tissues. This review considers intracellular processing of neuronal POMC as a key checkpoint that controls flux through hypothalamic melanocortin receptor pathways. Regulation of the convertase, proprotein convertase (PC)-1/3, which cleaves POMC is likely to determine the extent of POMC processing. Reduced PC1/3 activity, in both humans and rodents, leads to reduced melanocortin signaling and hence obesity. In contrast to POMC, posttranslational processing of proagouti-related peptide, an endogenous melanocortin-4 receptor antagonist, is efficient and is unlikely to represent a regulatory checkpoint. Because POMC is fully processed to ACTH and MSH peptides in secretory vesicles, unprocessed POMC, which is released from cells, must exit via an unregulated constitutive pathway. Therefore, the targeting of POMC to secretory granules controls the extent of POMC cleavage. There is evidence that PC1/3 is involved in cleavage of POMC in the trans-Golgi network and regulation of trafficking to the secretory pathway, in which it subsequently cleaves POMC to the melanocortin peptides. This would suggest that -MSH and ß-MSH may be subject to alternative sorting mechanisms, leading to heterogeneity in secretory granule content in POMC-producing cells. Overall, these studies implicate POMC processing as a key regulatory mechanism in the control of energy homeostasis.
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Introduction
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INTRACELLULAR POSTTRANSLATIONAL CLEAVAGE of inactive precursor proteins (particularly hormones and neuropeptides) by subtilisin-related proprotein convertases (PCs) (1) is very important in three respects. First, it enables cells to diversify the products of their genes. In many cases, mammalian precursor proteins can give rise to several bioactive peptides with different functions. Second, it ensures that bioactive peptides are produced only in tissues and cells in which they are required. Third, recent evidence suggests that posttranslational cleavage events are tightly regulated as an additional mechanism to control endocrine pathways. For example, activation of TRH receptors is coordinated with metabolic requirements by adjusting the rate and extent of TRH processing (2). This is achieved by tight tissue-specific regulation of two neuroendocrine-specific PCs, PC1/3 and PC2. The purpose of this review was to evaluate evidence that proopiomelanocortin (POMC) and agouti-related peptide (AGRP) processing is also regulated in this way to control flux through melanocortin signaling pathways.
POMC is a good example of a prohormone that yields several important peptides with differing functions. It is expressed principally in the pituitary gland, skin, and hypothalamus (3). POMC is processed by PC1/3 to generate proACTH and ß-lipotropin (ß-LPH). ProACTH is further cleaved by PC1/3 to N-terminal proopiocortin (N-POC), joining peptide, and ACTH (Fig. 1
). PC2 is then able to cleave ACTH 1–39 to generate ACTH 1–17 and corticotrophin-like intermediate lobe peptide, and a number of posttranslational modifications of ACTH 1–17 result in -MSH. N-POC is processed to 
-MSH, and in humans, but not rodents, -lipotrophin is processed to ß-MSH (Fig. 1). There is considerable complexity in this processing pathway, which is beyond the scope of this review. In mice lacking PC1/3, other prohormone convertases are able to cleave the dibasic amino acids to generate ACTH and joining peptide (4). It would appear that PC2 is capable of cleaving joining peptide and ACTH because these peptides are reduced in the hypothalamus of mice lacking PC2 (5). It is also known that PC1/3 can be inhibited by proSAAS, which is a neuroendocrine-specific inhibitor (6), and PC2 is inhibited by 7B2 (7). Tissue-specific processing of POMC is important for conferring specificity on the production of specific peptides. In the anterior pituitary gland, ACTH is produced and not cleaved further due to the absence of PC2. In the hypothalamus (8) and skin (9), POMC processing is more extensive. Processing follows a similar pattern in the intermediate lobe of the pituitary, which is very distinctive in rodents but less so in humans, except in the fetus.
ACTH secreted from the anterior pituitary, acts at the melanocortin-2 receptor (MC2-R) in the adrenal gland to regulate steroidogenesis (10). -MSH produced locally in the skin acts to control melanogenesis and thermoregulation via the MC1-R (11) and MC5-R (12), respectively. In the hypothalamus, -MSH and ß-MSH act at the MC3-R (13) and MC4-R (14) to control body weight.
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Is POMC Processing Important in Regulating Body Weight?
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The MSH/MC4-R axis in the hypothalamus represents a key regulatory checkpoint in energy homeostasis. Unlike many other genes implicated in body-weight regulation, heterozygous loss-of-function mutations in POMC (15, 16) and MC4-R (17, 18) lead to obesity in rodents and humans, indicating a level of dose sensitivity. Moreover, a plethora of studies have shown that POMC expression is reduced in situations of negative energy balance (reviewed in Ref. 19). Because reduced MC4-R signaling increases body weight, stimulation of this pathway could represent a therapeutic strategy to combat obesity. Consequently, the use of MC4-R agonists has been explored as a potential antiobesity treatment (reviewed in Ref. 20). Although effective, such an approach is dogged by potential side effect issues. Could alternative strategies be used that stimulate POMC-derived peptide synthesis in the brain? Studies in rodents have shown that exogenous overexpression of POMC in the hypothalamus protects against obesity (21, 22, 23). Therefore, in principle, strategies that stimulate increased processing of endogenous POMC in the hypothalamus could be beneficial by increasing melanocortinergic activation. With this in mind, it is interesting to note that POMC processing, in humans and in rats, is actually incomplete and is regulated to control the concentrations of melanocortinergic peptides. Thus, a detailed understanding of how the POMC processing cascade is regulated could offer novel potential therapeutic opportunities.
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POMC Processing Is Incomplete in the Pituitary, Hypothalamus, and Skin
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The degree of processing of propeptides can vary significantly. For example, proinsulin is efficiently processed such that mature insulin concentrations are approximately 5-fold higher than proinsulin in the circulation of normoglycemic humans (24). On the other hand, other propeptides, such as prorenin, are inefficiently cleaved (25). Only 25–30% of prorenin is converted to active renin. The observation that certain proproteins are only partially processed suggests that regulation of processing could be as important as, if not more important, than transcriptional regulation as a means of controlling the synthesis of bioactive peptides. Could this be the case for POMC?
In the past, analysis of POMC processing has been hampered by sequence homology of different POMC-derived peptides and low avidity of polyclonal antisera. To overcome these problems and bypass the necessity for complex chromatographic techniques, a sandwich assay based on two monoclonal antibodies directed against ACTH was developed (26). Subsequently a panel of these assays were developed for POMC and derived peptides (27, 28, 29). This panel of assays allowed direct measurement of relative levels of different POMC-derived peptides in the human circulation under basal conditions. Strikingly, unprocessed POMC was the most predominant peptide in the circulation, indicating that POMC is inefficiently processed in the pituitary (29). Indeed, high levels of unprocessed POMC were found in primary rat pituitary cells and AtT20 pituitary adenoma cells (30). Similarly, in the skin, POMC processing is incomplete. It has recently been shown that cultured human epidermal keratinocytes and melanocytes secrete high levels of unprocessed POMC, which is able to influence melanogenesis and melanocyte differentiation (31).
The extent of POMC processing in the hypothalamus has also been assessed by measuring peptides in cerebrospinal fluid (csf). In human csf, POMC levels are in considerable excess of derived peptides (32). More recently central POMC processing has been analyzed in the rat by measuring POMC, ACTH, and -MSH levels in csf and hypothalamic extracts (33). These studies showed that POMC processing is incomplete, and significant levels of POMC are secreted from hypothalamic neurons. Importantly, the ratio of POMC to derived peptides in csf is significantly higher in obese vs. lean, and fasted vs. fed, rats, indicating that POMC processing is down-regulated in situations of negative energy balance during which leptin levels are low. This has been confirmed in rats that were fasted, in which the POMC-derived peptides were decreased and, importantly, PC1/3 was decreased in the arcuate nucleus. These effects were reversed by treatment with leptin. Interestingly, in the nucleus of the solitary tract in the medulla, there was a large amount of a 28.1-kDa form thought to be POMC, and therefore, the processing was less efficient than in the arcuate nucleus. Both POMC and POMC-derived peptides accumulated in fasting conditions in the nucleus of the solitary tract, and this was not reversed by leptin (34).
Based on these observations, it seems that excess POMC is synthesized in the pituitary, skin, and hypothalamus. This may be to ensure that there is always a readily available store of ligands for the melanocortin receptors that can be rapidly secreted in response to physiological requirements. Clearly only a proportion of POMC is proteolytically converted into ACTH and MSH peptides, and the excess POMC is secreted. Therefore, the extent of POMC processing is likely to be rate limiting in the regulation of melanocortinergic signaling.
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ProAGRP Processing Occurs Efficiently in the Hypothalamus
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Unusually for G protein-coupled receptors, the melanocortin receptors possess endogenous antagonists that have opposite functions to POMC-derived ligands. The endogenous antagonist for the MC4-R is AGRP, a 132-amino acid peptide that exhibits a very similar, although more restricted, neuroanatomical distribution to POMC (35, 36, 37). It has recently been demonstrated that AGRP is cleaved before secretion, predominantly by PC1/3, to generate AGRP83–132 and one or more amino-terminal fragments (38). AGRP83–132 antagonizes the MC4-R, whereas the biological function, if any, of amino-terminal fragment(s) has yet to be established, although it has been suggested that they play an independent role in body weight regulation (39, 40). Given that full-length AGRP is less potent as an MC4-R antagonist than AGRP83–132 (38), it is possible that posttranslational processing of AGRP, like POMC, is regulated to control melanocortinergic flux. However, this seems unlikely because AGRP is very efficiently processed to completion in the brain (38). Therefore, transcriptional regulation is probably more important for AGRP than POMC. Indeed, acute changes in energy balance have a more profound influence on AGRP gene expression than POMC gene expression (reviewed in Ref. 41). Furthermore, hypothalamic AGRP, but not POMC, expression exhibits a clear diurnal rhythm in rats that coincides with nocturnal feeding activity (42). Therefore, the regulation of melanocortin signaling appears multifaceted, with both transcriptional and posttranslational mechanisms affecting ligand availability. Posttranslational regulation is likely to be proportionally more important in the regulation of the POMC, compared with the AGRP arm of the homeostatic circuit.
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PC1/3 Regulates the Extent of POMC Processing and Is Strongly Implicated in the Pathogenesis of Obesity
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How do POMC-producing cells control the extent of POMC cleavage? This is likely to be achieved by tight regulation of PC1/3. In humans, PC1/3 deficiency leads to increased body weight. Two patients with PC1/3 deficiency have been identified (43, 44). Strikingly, in both cases, the absence of functional PC1/3 resulted in gross obesity. POMC processing is disrupted in these individuals, thereby reducing secreted levels of melanocortin peptides. It is likely that disrupted POMC processing is the underlying cause of obesity. However, because the processing of many prohormones is affected in these patients, a definitive link between POMC processing and obesity cannot be concluded.
Interestingly, gross obesity has also been observed in a PC1/3-deficient mouse model (45). These mice carry a missense mutation (N222D) in the PC1/3 gene that reduces enzymatic activity but does not completely inactivate the PC1/3 protein (45). Both PC1/3N222D/N222D and PC1/3N222D/+ mice are obese due to reduced POMC processing in the hypothalamus. In contrast to N222D mice, PC1/3 null mice are not obese but display multiple endocrine defects (38, 46, 47, 48). The comparison of PC1/3 null and N222D mice shows that complete absence of PC1/3 has predictably severe consequences for the processing of many prohormones, whereas reduced PC1/3 activity seems to disproportionately affect POMC processing, leading to a range of phenotypic effects consistent with reduced melanocortin signaling. Therefore, it seems that changes in PC1/3 activity play a particularly important role in regulating POMC processing, compared with other substrates such as proinsulin and proGHRHm which are more efficiently processed and are therefore less severely affected by reduced PC1/3 activity. This hypothesis is supported by the observation that PC1/3 heterozygote mice (+/–) are obese but otherwise develop normally (46). Also, interestingly, partial PC1/3 activity is suspected in both reported cases of human PC1/3 deficiency (43, 44), which could explain the differences in observed phenotype, compared with PC1/3 null mice.
The potential importance of PC1/3 in controlling melanocortin signaling is underscored by observations in several rodent models of obesity. Hypothalamic expression levels of PC1/3 are down-regulated in ob/ob mice (49), CpeFat mice (50), and NhlH2 knockout mice (51). PC1/3 is also down-regulated in the hypothalamus of fasted vs. fed rats (2). The molecular mechanism underlying this regulation is not understood, although PC1/3 is a downstream target of leptin signaling (2, 49, 52). It is also possible that PC1/3 is regulated at the posttranslational level by changes in expression of the endogenous PC1/3 inhibitor, proSAAS (2). It seems that PC1/3 activity in POMC neurons is carefully controlled to coordinate melanocortin release with physiological requirement. Perturbations in this system may contribute to the development of obesity. This is supported by our observations that the extent of POMC processing is decreased in fasted vs. fed rats (33). There is also evidence that posttranslational processing is involved in the control of body weight in seasonal adaptation in Siberian hamsters (53).
In contrast to studies on the role of PC1/3, there is no evidence linking PC2 with the pathogenesis in obesity. PC2 null mice are not obese (54), and hypothalamic levels of PC2 protein, unlike PC1/3, are not decreased in fasted vs. fed rodents (2). It is likely that processing events catalyzed by PC1/3, rather than PC2, are key to controlling the extent of POMC processing.
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How Are the Dynamics of POMC Processing and Sorting Regulated?
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There are two explanations for the observation that POMC is incompletely processed. It is possible that only a proportion of POMC is converted into melanocortin peptides within secretory granules. Consequently, when secretory granules release their contents, POMC is cosecreted with processed peptides. This possibility, however, seems unlikely. Several reports (29, 30, 55) have shown that POMC is not secreted in response to secretagogues, implying that it is released in an unregulated constitutive or constitutive-like pathway. Moreover, pulse-chase experiments indicate that POMC is entirely converted to ACTH in the secretory granules of AtT20 cells (55).
It is more likely that sorting/retention of POMC from the trans-Golgi network (TGN) to immature secretory granules is the key regulatory step that governs the extent of POMC processing. There is considerable controversy regarding the mechanism(s) by which POMC is sorted and retained in the regulated secretory pathway. Currently the majority of studies support a sorting-for-entry model in which targeting to granules is triggered in the TGN (55). It is likely that POMC sorting is largely mediated via an amino-terminal amphipathic loop that acts as a sorting signal motif (56), which has been proposed to bind to carboxypeptidase E as a putative sorting receptor (57). However, mutagenesis experiments indicate that POMC does not solely rely on a single sorting signal (58). A recent study has indicated that distinct sorting signals within the same protein can act in concert to determine sorting efficiency (25). On balance, therefore, POMC must contain sorting signals, in addition to the amino terminus, that underlie variation in the extent of POMC processing under different physiological circumstances (Fig. 2).
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FIG. 2. Posttranslational cleavage of POMC follows a strict temporal and spatial order in the cell. After synthesis, POMC is sorted into the endoplasmic reticulum and subsequently the TGN. Here, POMC is partially cleaved to generate proACTH (precursor of ACTH and -MSH) and ß-LPH [precursor of ß-MSH and ß-Endorphin (ß-End)]. It may be that the initial cleavage event is rate limiting and determines the proportion of POMC that is processed in the secretory pathway. Unprocessed POMC is constitutively secreted and therefore not subject to regulatory factors. ProACTH and presumably ß-LPH are sorted from the TGN into secretory granules, although the mechanism is not fully understood. An amphipathic loop at the amino-terminal end of proACTH is thought to be an important sorting signal, but this cannot be responsible for ß-LPH sorting. In secretory granules, PC1 and PC2 are fully activated and generate -MSH, ß-MSH, -MSH, and ß-End. Because proACTH and ß-LPH are likely to rely on independent sorting signals, -MSH and ß-MSH may be sorted into distinct subgroups of secretory granules. Alternatively, it may be that some POMC is sorted into secretory vesicles, and all the cleavage events occur in the secretory vesicles, which would result in -MSH and ß-MSH in the same secretory granules.
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Recent studies have indicated that partial PC1/3 activity in the TGN regulates trafficking of other prohormones such as proTRH (59), VGF (60), and pro-islet amyloid polypeptide (61). Removal of the initial cleavage site on the proTRH polypeptide diverted the peptides to the constitutive pathway, suggesting that this cleavage is important for directing the peptides to the constitutive pathway. Given that changes in PC1/3 activity disproportionately affect POMC processing (discussed above), it is likely that PC1/3 could play a prominent role in regulating sorting/retention of POMC. Indeed, overexpression of PC1/3 in AtT20 cells leads to more extensive cleavage of POMC to ACTH (62). Conversely, preliminary data from our laboratory have shown that inhibition of PC1/3 by RNA interference reduces regulated secretion of ACTH and increases constitutive secretion of POMC in AtT20 cells (our unpublished data). These data indicate that PC1/3 regulates the extent by which POMC is sorted/retained in the secretory pathway, and is subsequently processed into ACTH.
How could changes in PC1/3 expression/activity influence the intracellular trafficking of POMC? One possibility is that partial activity of PC1/3 in the TGN influences subsequent sorting events (Fig. 2
). It is well known that PC1/3 is synthesized as an inactive precursor. The prosegment is rapidly removed in the endoplasmic reticulum, but PC1/3 does not become fully activated until it reaches immature secretory granules and undergoes an autocatalytic cleavage event that removes its carboxyl terminus (63, 64). However, PC1/3 is partially active before autocatalysis (65, 66). Consequently, POMC is partially processed to proACTH and ß-LPH in the TGN (67, 68). Because this cleavage event occurs at low efficiency, the level of expression of PC1/3 in the TGN is likely to have a rate-limiting role in the synthesis of proACTH and ß-LPH. The extent of this initial cleavage event could influence the efficiency of subsequent sorting into the secretory pathway. Given the effect of reduced PC1/3 on POMC processing in vivo, it is likely PC1/3 plays a significant role in regulating POMC trafficking. It is not clear how proSAAS, a potent endogenous PC1 inhibitor, would influence this process. Overexpression of proSAAS has been shown to reduce the rate of POMC processing in AtT20 cells (6), although it did not have an effect on the steady-state content of POMC-derived peptides (69). Further studies will be required to confirm this hypothesis.
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The Impact of POMC Processing and Trafficking on Generation of -MSH and ß-MSH
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As discussed above, POMC is partially cleaved in the TGN to generate proACTH (precursor of -MSH) and ß-LPH (precursor for ß-MSH in humans and ß-endorphin). Because the amino-terminal loop is present on proACTH, it cannot be totally responsible for ß-LPH sorting. Therefore, -MSH and ß-MSH/ß-endorphin may be sorted by different mechanisms, possibly into different subpopulations of secretory granules (Fig. 2). Such a phenomenon has been described for various coexpressed neuropeptides (70, 71), including ones derived from the same precursor (72). Independent trafficking/secretion of -MSH and ß-MSH in POMC neurons could have major physiological implications because ß-MSH, in addition to -MSH, plays a key role in control of energy balance in humans (73, 74, 75). Furthermore, ß-endorphin is important in energy homeostasis and may complement (76), or antagonize (77), melanocortin action. For this reason it is important to determine the nature of sorting signals that mediate ß-LPH trafficking. Of particular interest are the series of dibasic sites within ß-LPH. Dibasic sites have shown to be important sorting signals for several propeptides (60, 77, 78, 79, 80, 81). However, the role of dibasic residues in POMC trafficking has not been established.
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Summary
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Although transcriptional control of POMC undoubtedly plays a role in regulating melanocortin signaling, posttranslational regulation is also likely to be important. This possibility has not been subject to intense scrutiny in the literature, largely due to technological difficulties in quantifying the extent of POMC processing. However, the use of precise assays has circumvented this issue and has shown that processing is incomplete and is regulated with respect to physiological requirements. Dysregulated POMC processing is implicated in the pathophysiology of obesity and is related to changes in PC1/3 activity. Specific manipulation of POMC processing in a clinical setting would undoubtedly be a challenging goal, but further research could open exciting new vistas in the treatment of obesity and other endocrine diseases.
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Acknowledgments
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We are grateful to Dr. Rob Oliver, Anne Warhurst, and Tom Day for contributions to the experimental data.
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Footnotes
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This work was supported by the Wellcome Trust and AstraZeneca.
Disclosure Summary: The authors collaborate with and receive research funding from AstraZeneca.
First Published Online June 21, 2007
Abbreviations: AGRP, Agouti-related peptide; csf, cerebrospinal fluid; ß-LPH, ß-lipotropin; MC-R, melanocortin receptor; N-POC, N-terminal proopiocortin; PC, proprotein convertase; POMC, proopiomelanocortin; TGN, trans-Golgi network.
Received December 14, 2006.
Accepted for publication June 14, 2007.
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November 1, 2008;
93(11):
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Abstract
Introduction
