Q J Med 2000; 93: 7-14
© 2000 Association of Physicians
Reviews |
The role of melanocortin signalling in the control of body weight: evidence from human and murine genetic models
From the Departments of Medicine and Clinical Biochemistry, Cambridge Institute for Medical Research, Addenbrooke's Hospital, University of Cambridge, and 1 Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, UK
Professor S. O'Rahilly, Departments of Medicine and Clinical Biochemistry, Level 5, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK
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Summary |
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 Top Summary IntroductionGenetic defects involving over...Genetic defects of POMC...Genetic defects of POMC...Genetic defects of melanocortin...Summary and conclusionsReferences |
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The peptide products of the pro-opiomelanocortin (POMC) gene have established roles in the control of physiological processes as diverse as adrenal steroidogenesis, skin pigmentation, analgesia and inflammation. In the last 5 years, evidence accumulated from murine and human genetic models of disrupted melanocortin signalling has firmly established a central role for a population of hypothalamic neurons expressing POMC in the control of appetite and body weight. Of the five known melanocortin receptors, the MC4R has been most closely linked to body weight regulation. While a-MSH is active at this receptor and suppresses appetite after central injection, important roles for other POMC-derived products have not been excluded. The development of pharmacological agonists acting on, or mimicking, the hypothalamic melanocortinergic pathway may provide exciting opportunities for the therapy of human obesity.
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Introduction |
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TopSummaryIntroductionGenetic defects involving over...Genetic defects of POMC...Genetic defects of POMC...Genetic defects of melanocortin...Summary and conclusionsReferences |
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The POMC gene is expressed at physiologically significant levels in a number of mammalian tissues including anterior and intermediate pituitary, skin, the immune system and hypothalamic neurons.1–3 In these tissues the precursor peptide, POMC, is cleaved into a range of smaller peptides including adrenocorticotropin (ACTH), ß-endorphin and
-, ß- and 
-melanocyte-stimulating hormones (MSH) (Figure 1
). The repertoire of products derived from POMC by any tissue is determined by the specificities of the endoproteases (convertases) expressed in the secretory pathway.4,5 Thus, anterior pituitary corticotrophs express prohormone convertase 1 (PC1) and cleave POMC to ACTH, while melanotrophs in the intermediate lobe of lower animals, express prohormone convertase 2 (PC2) and cleave ACTH further to yield -MSH. The physiological roles of the various melanocortin peptides have been defined with varying degrees of certainty. Thus, ACTH, secreted from the anterior pituitary is the major controller of adrenal steroidogenesis.6 In amphibians and rodents, -MSH from the intermediate lobe of the pituitary is involved in the control of skin and coat pigmentation.7 Mammals also express POMC in skin, and locally secrete not only -MSH but also ß- and -MSH, ACTH and ß-endorphin, although their physiological functions are not established.8 The importance of at least some of these peptides to human pigmentation is revealed by the association of variants of the human melanocortin-1 receptor with red hair and fair skin.9–11 The physiological roles of central ß- and -MSH, CLIP and ß-lipotropin are also less than clear. Beta-endorphin, although a product of the POMC gene, does not share the receptor binding sequence common to the melanocortin peptides, and interacts with opioid receptors.
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The actions of the melanocortin peptides are mediated by a family of five G-protein-coupled, seven-transmembrane-domain receptors. The sites of their expression and presumed physiological roles are summarized in Table 1
. Of note, the MC3R12,13 and the MC4R14,15 are expressed in areas of the brain that have been implicated in the control of feeding. The first evidence that central melanocortinergic pathways may be involved in feeding came from studies of rodents in which the intracerebroventricular (ICV) administration of -MSH led to suppression of food intake.16,17 More recently, ICV injection of the cyclic hepta-peptide MTII, a melanocortin agonist active at the MC3R and MC4R, reduced food intake in a number of rodent models, this effect being blocked by the specific antagonist SHU9119.18,19 The central administration of SHU9119 increases food intake, providing evidence that endogenous melanocortins are indeed likely to be involved in appetite control.19 The neuroanatomy of hypothalamic neurons expressing POMC is consistent with a putative role for such cells in the control of energy balance. Thus POMC-expressing neurons within the arcuate nucleus (ARC) project extensively to specific brain areas thought to regulate feeding, including the paraventricular nucleus, lateral hypothalamus, dorsomedial nucleus, ventromedial hypothalamic nucleus and dorsal motor nucleus of the brainstem (Figure 2). Immunocytochemistry and in situ hybridization studies indicate that 40% of POMC-containing neurons express mRNA for the long form of the leptin receptor.20 POMC expression in the arcuate nucleus is increased by leptin administration and reduced in hypoleptinaemic states such as fasting or in the ob/ob mouse.21 Leptin administration to the ob/ob mouse restores POMC expression in the rostral arcuate nucleus.22 Interestingly, a large percentage of POMC-containing neurons also express the recently described anorexic peptide CART (cocaine and amphetamine regulated transcript).23 CART expression parallels POMC expression in response to leptin treatment.24 Furthermore, ICV injection of recombinant CART into both rats and mice inhibits both normal and starvation-induced feeding.24 Conversely, following central administration of anti-serum against CART in rats, the feeding response was increased.24 Thus, this novel neuropeptide appears to co-operate with POMC in mediating the appetite suppression effects of leptin.
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Genetic defects involving over-expression of melanocortin antagonists |
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TopSummaryIntroductionGenetic defects involving over...Genetic defects of POMC...Genetic defects of POMC...Genetic defects of melanocortin...Summary and conclusionsReferences |
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The first genetic evidence that melanocortin signalling may be important for the control of mammalian body weight came from studies of the agouti (yellow) mouse. The genetic basis for this dominantly-inherited murine phenotype was elucidated in 1994,25 and was the first of a number of such gene discoveries in rodent obesity that have helped to catapult the field of obesity into the forefront of contemporary biomedical research. Yellow agouti mice have a pleiotropic syndrome which is characterized by obesity, hyperphagia, hyperinsulinaemia, hyperglycaemia in males and a yellow coat colour.26–28 The phenotype in these mice is caused by inherited promoter rearrangements at the agouti locus that result in constitutive ectopic expression of the agouti peptide.27–31 Agouti is a 131-amino-acid protein which is normally secreted only within the hair follicle, where it acts in conjunction with MSH to regulate hair pigmentation, producing the murine wild-type coat coloration of black hairs with a subapical yellow band.26,27 In the absence of the agouti protein, MSH binds to the melanocortin-1 receptor (MC1R) on the surface of melanocytes, leading to the production of brown-black (eumelanin) pigment. Agouti functions as a paracrine molecule, antagonizing the MCIR and inducing a switch from eumelanin to yellow-red (phaeomelanin) pigment production.25 The obesity phenotype seen in the agouti syndrome is not dependent on the synthesis of phaeomelanin or the disruption of MC1R signalling, since Avy mice carrying a gain-of-function MC1R mutation are black yet still obese,32 while mice lacking MC1R activity are yellow but not obese.33
A hypothesis for the mechanism of this obesity syndrome was that ectopic agouti expression resulted in aberrant antagonism of other melanocortin receptors in areas of the brain known to be involved in the control of food intake and body weight.15,25 Agouti potently antagonizes the action of melanocortin peptides at the MC1R, the MC4R, and to a lesser degree the MC2R, but not at the MC3R or MC5R.25,34 This proposed mechanism for the phenotype of the agouti syndrome was supported by the identification of the Agouti-related protein or AGRP, a hypothalamic neuropeptide found in both rodents and humans, which shares high sequence homology with Agouti.35,36 AGRP was found to be a melanocortin receptor antagonist which primarily antagonizes the MC3R and MC4R.36 Ubiquitous overexpression of human AGRP results in an obese mouse sharing the identical phenotype to the agouti mouse, but possessing a normal coat colour.36 AGRP mRNA is expressed almost exclusively in the arcuate nucleus of the hypothalamus,35,36 and it appears that AGRP is co-expressed in neurons containing the potent orexigenic peptide neuropeptide Y (NPY).37 AGRP mRNA levels are five to ten times higher in fasted animals and in ob/ob mice, and suppress to normal levels after leptin treatment.35,38
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Genetic defects of POMC synthesis |
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TopSummaryIntroductionGenetic defects involving over...Genetic defects of POMC...Genetic defects of POMC...Genetic defects of melanocortin...Summary and conclusionsReferences |
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The first direct evidence for the involvement of melanocortin peptides in the control of human appetite came from the description of two patients with defects in the POMC gene.39 One proband was compound heterozygous for two mutations which prevented synthesis of ACTH and
-MSH, and the second unrelated proband was homozygous for a nucleotide transversion upstream of the start codon which interferes with translational initiation by introducing an additional start site. The affected children presented with the metabolic consequences of hypocortisolaemia in the first few months of life, and had undetectable plasma cortsiol and ACTH. Glucocorticoid treatment reversed the severe metabolic derangement, but progressive obesity associated with hyperphagia developed in both children. Intriguingly, both children had very pale skin and red hair. The failure of adrenal steroidogenesis was a predictable consequence of the lack of ACTH action on the adrenal MC2R. Mutations in the MC1R are common in red-haired humans and presumably the lack of endogenous ligand for the MC1R was responsible for the skin/hair phenotype.9,11 The normal phenotype of the heterozygous parents indicates a recessive mode of inheritance. Presumably the hyperphagia and weight gain is the result of lack of melanocortinergic signalling within the appetite control centres in the brain. Of interest, no other behavioural or neurological dysfunction is apparent in these children, implying that appetite control may be the dominant function of POMC-expressing neurons within the central nervous system. These children provide the first compelling evidence for an important role of POMC in the control of human appetite. |
Genetic defects of POMC processing |
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TopSummaryIntroductionGenetic defects involving over...Genetic defects of POMC...Genetic defects of POMC...Genetic defects of melanocortin...Summary and conclusionsReferences |
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The fat/fat mouse displays a recessive syndrome of adult-onset marked obesity associated with high circulating concentrations of POMC and proinsulin.40 The defective prohormone processing is due to an inactivating missense mutation in carboxypeptidase E (CPE), an enzyme which co-operates with prohormone convertases in the proteolyic maturation of many hormone and neuropeptide precursors.41 Interestingly, transgenic replacement of CPE activity in the islets of fat/fat mice corrects the hyperproinsulinaemia, but does not alter their obesity, indicating that islet dysfunction is unlikely to be its cause.40 While deficient melanocortin signalling within the central nervous system, due to defective processing of POMC, is an attractive candidate to explain the obesity, the pathophysiology must be complex, because CPE dysfunction will affect the processing of numerous neuropeptides, some of which, e.g. GLP1 and neurotensin, have putative roles in the control of satiety whilst others, e.g. neuropeptide Y and melanin concentrating hormone, are orexigenic.42–44 The cause of the uniquely late-onset obesity of the fat/fat mouse remains a tantalising mystery. Despite searching, mutations of the human CPE gene have not been found.45
In 1995, we reported a woman with a novel syndrome suggestive of defective prohormone processing.46 Her clinical features included extreme childhood obesity, reactive hypoglycaemia and hypogonadotrophic hypogonadism. In her plasma, the ratios of proinsulin to insulin, and POMC to ACTH were enormously elevated. Subsequently, she was found to be compound heterozygous for PC1 mutations.47 As with the fat/fat mouse, while this patient provides evidence which suggests that the obesity and hyperphagia may have arisen from failure of POMC processing, the broader role of PC1 implies that other candidate molecules may be involved, for example GLP-1.48,49 Interestingly, unlike the human with PC1 mutations, PC2 null mice are not obese, despite reports that PC2 is necessary for processing of POMC to MSH and the formation of other anorexic peptides such as CRH and neurotensin5.50–52 A possible explanation may lie in the particular role PC2 has in cleaving ß-endorphin from POMC and enkephalin from proenkephalin. Mature enkephalin levels in the brains of PC2 null mice are markedly reduced and endogenous opioid pathways may have a role in signalling within orexigenic networks.44,53
We recently reported the development of obesity in a child first described by Nussey and co-workers, who has undetectable plasma ACTH, markedly elevated plasma POMC and normal proinsulin processing.54,55 The genomic sequences of POMC and PC1 are normal, and the phenotype is distinct from that of PC2 or CPE deficiency. Though the precise nature of the defect in this child remains obscure, she provides further suggestive evidence that defective processing of POMC is associated with obesity in man.
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Genetic defects of melanocortin receptor signalling |
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TopSummaryIntroductionGenetic defects involving over...Genetic defects of POMC...Genetic defects of POMC...Genetic defects of melanocortin...Summary and conclusionsReferences |
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The phenotypic effects of disruption of the MCIR, MC2R and MC5R do not involve alterations in energy balance and have their main effects on pigmentation, adrenal function and sebaceous gland secretion, respectively.33,56,57 In contrast, targeted disruption of the MC4R in mice results in an obesity syndrome characterized by hyperphagia, hyperinsulinaemia, hyperglycaemia, and increased linear growth, with no abnormality of the reproductive or adrenal axes.58 MC4R knockout mice do not respond to the anorectic effects of the agonist MTII.59 Heterozygotes for the null MC4R allele exhibit a phenotype intermediate between that of wild-type and homozygous littermates.58 These data provide strong evidence that the MC4R receptor is involved in the mediation of the effects of melanocortins on appetite. Results from the knock out of the MC3R are eagerly awaited, and it remains possible that this receptor, which is widely expressed in the CNS, may also play a role in some aspects of energy balance.
Subsequently, we and others have identified a number of different families in which mutations in the human MC4R are associated with severe early onset obesity.60–63 It is notable that most of the affected patients reported thus far have been heterozygous for their respective mutations, and that these obese subjects show no evidence of impaired adrenal or reproductive function, all of which are consistent with the rodent model data. The finding of a phenotype associated with heterozygous mutations in the MC4R is consistent with the murine data, and suggests that this receptor may represent a tightly regulated control point in the homeostatic control of body weight. The fact that heterozygous null mutations result in an obese phenotype in both humans and mice is highly suggestive of haplo-insufficiency rather than dominant negativity, and indicates that the regulatory system is sensitive to quantitative variation in MC4R expression.
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Summary and conclusions |
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TopSummaryIntroductionGenetic defects involving over...Genetic defects of POMC...Genetic defects of POMC...Genetic defects of melanocortin...Summary and conclusionsReferences |
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Accumulating evidence from humans and mice with genetic defects in POMC synthesis, processing and melanocortin receptor signalling clearly points to an important role for the hypothalamic melanocortinergic neuronal population in the control of appetite and energy balance. Is there any evidence that dysfunction of this pathway might contribute to more common forms of human obesity? Intriguingly, a number of independent linkage studies attempting to identify quantitative trait loci (QTLs) involved in the determination of obesity and obesity-associated traits have come up with positive LOD scores for a locus at chromosome 2p21 which encompasses the POMC gene. Thus Comuzzie et al. (1997), studying a Mexican-American population, reported that this locus accounted for 47% of the variation in serum leptin levels.64 Subsequent studies on French families65 as well as a population of African Americans66 have reported the same association. Of course, this region of chromosome 2 encompasses many more genes than POMC and there is, as yet, no proof that sequence variations in or around POMC are responsible for these findings.
The potential therapeutic implications of this body of work are readily apparent and have not been lost on the pharmaceutical industry. Previous pharmacological approaches to the development of appetite suppressants involving manipulation of serotoninergic and or noradrenergic signalling have run aground as a result of the toxicity associated with the interference with the broader functions of these transmitters in other tissues and other CNS pathways. Given the fact that the MC4R has a much more anatomically restricted pattern of expression and given the relatively `pure' obesity phenotype resulting from its dysfunction, this receptor clearly represents an exciting potential therapeutic target.
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References |
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TopSummaryIntroductionGenetic defects involving over...Genetic defects of POMC...Genetic defects of POMC...Genetic defects of melanocortin...Summary and conclusionsReferences |
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