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Obesity: Special Feature |
University Departments of Medicine and Clinical Biochemistry, Cambridge Institute of Medical Research, Addenbrooke’s Hospital, Cambridge, United Kingdom CB2 2QQ
Address all correspondence and requests for reprints to: Dr. Stephen O’Rahilly, University Departments of Medicine and Clinical Biochemistry, Box 232, Addenbrooke’s Hospital, Cambridge, United Kingdom CB2 2QR. E-mail: sorahill{at}hgmp.mrc.ac.uk.
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Abstract |
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 Top Abstract IntroductionDefects in the synthesis...Defects in the action...ConclusionsReferences |
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MSH. However, a rapidly expanding body of work has established that POMC-derived peptides synthesized in neurons of the hypothalamus play a central role in the control of energy homeostasis. We review how inherited abnormalities in POMC synthesis and processing and defects in the action of POMC-derived peptides in both humans and mice have helped shape our current understanding of the importance of the melanocortin system in human energy balance. |
Introduction |
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TopAbstractIntroductionDefects in the synthesis...Defects in the action...ConclusionsReferences |
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). The precise repertoire of POMC-derived products from any particular tissue is largely dependent on the range of processing enzymes expressed in that tissue. Thus, pituitary corticotrophs express prohormone convertase 1 (PC1), but not PC2, resulting in the production of N-terminal peptide, joining peptide, ACTH, and ß-lipotropin. In contrast, the expression of PC2 within the hypothalamus leads to the production of -, ß-, and 
MSH, but not ACTH.
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POMC neurons produce the anorectic peptide MSH together with cocaine- and amphetamine-related transcript, whereas a separate group expresses the orexigens neuropeptide Y and agouti-related protein (AGRP). AGRP is a hypothalamic neuropeptide that is a potent MC3R and MC4R antagonist. Activation of the neuropeptide Y/AGRP neurons increases food intake and decreases energy expenditure, whereas activation of the POMC neurons decreases food intake and increases energy expenditure (3). The long isoform of the leptin receptor is highly expressed on these arcuate neurons, and leptin regulates these two neuronal populations in a reciprocal manner (3). For example, suppressed levels of leptin after a fast decrease POMC mRNA and increase AGRP mRNA in the hypothalamus (3).
From the arcuate nucleus, these two populations of neurons project to other brain areas that contain second order neurons expressing neuropeptides involved in energy homeostasis. In particular, there are extensive projections to several hypothalamic regions, including the lateral hypothalamus and the paraventricular nucleus. Cell bodies within the lateral hypothalamus contain the potent orexigenic peptide melanin-concentrating hormone, and neurons of the paraventricular nucleus express TRH. Thus, via this second order signaling, the melanocortin peptides are able to exert their effects.
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Defects in the synthesis and processing of POMC |
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TopAbstractIntroductionDefects in the synthesis...Defects in the action...ConclusionsReferences |
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In 1998, Krude et al. (4) provided the first description of humans congenitally lacking POMC gene products. One proband was a compound heterozygote for two nonsense mutations in exon 3, which would result in loss of ACTH, MSH, and ßMSH, although perhaps retaining MSH expression. However, as premature stop mutations frequently result in nonsense-mediated decay of mRNA, it is possible that no forms of MSH would be produced in this patient. A second patient was homozygous for a 5'-untranslated region mutation that introduced an additional out-of-frame start site, thus interfering with POMC translational initiation. As a consequence of ACTH deficiency, both subjects presented in early childhood with the metabolic consequences of hypocortisolemia. Both went on to develop severe, early-onset obesity associated with hyperphagia (due to reduced hypothalamic melanocortinergic signaling), and both probands had pale skin and red hair (the result of reduced signaling through MC1R on melanocytes in skin and hair follicles). Since the first description of loss of function mutations in the human POMC gene, Gruters’ group (5) has gone on to report three additional children with the same phenotype. One previously described translation initiation mutation, one new nonsense mutation, and two new frameshift mutations were found as either homozygotes or compound heterozygotes.
The same group have also recently reevaluated thyroid function in the first two children with POMC deficiency (5). Both had repeatedly elevated TSH levels, borderline reduced total T4 values, and normal responses to TRH stimulation testing suggestive of subclinical hypothyroidism of hypothalamic origin. These observations are in accordance with previous data (6), which propose the central melanocortin system to be a key junction in translating peripheral signals of energy balance into dynamic changes in hypothalamic-pituitary-thyroid axis function. Both children were treated with levothyroxine to normalize T4 values and bring TSH to the low normal/suppressed range, but this had no impact on their obesity. In an attempt to overcome the lack of hypothalamic melanocortin signaling and so ameliorate their obesity, these two initial probands also underwent a trial of treatment with intranasal ACTH 4–10, although neither a reduction in body weight nor a change in eating behavior was seen. However, this peptide fragment has been shown to have low affinity for the relevant melanocortin receptors (5).
We screened the coding region of the POMC gene in 262 Caucasian subjects with a history of severe obesity from childhood and identified two children who were heterozygous for a missense mutation (Arg236Gly) that disrupts the dibasic amino acid cleavage site between ßMSH and ß-endorphin (7). In a mini-meta-analysis of published studies that had screened the POMC gene in obese children, mutations disrupting this site were found in 0.9% of children with severe-onset obesity compared with only 0.2% of normal weight controls, suggesting that mutations at this site may make an appreciable contribution to the genetic predisposition to severe childhood obesity.
The Arg236Gly mutation completely prevents the normal processing of these two peptides, resulting in an aberrant ßMSH/ß-endorphin fusion peptide. In vitro studies revealed this fusion protein to have an affinity to MC4R comparable to that of - or ßMSH, but with a reduced ability to activate the receptor once bound. Thus, this mutation produces an aberrant fusion protein that has the capacity to interfere with central melanocortin signaling, and this may represent a novel mechanism of endocrine disease whereby a mutation results in a secreted ligand that can interfere with the actions of the endogenous ligand at its target receptor.
POMC knockout mice.
The first report of a mouse model with disruption of both alleles of the POMC gene (8) recapitulated the phenotype seen in humans, indicating that melanocortin pathways in humans and rodents subserve very similar functions in the regulation of energy homeostasis and adrenal function. Notably, peripheral administration of MSH to these mice greatly ameliorated the obesity. Although the researchers believed that their data best supported a peripheral effect of the administered melanocortin on energy expenditure, the data presented are as compatible with an effect on energy intake. We recently generated an independent line of mice lacking all POMC-derived peptides (Pomc–/–) that are also markedly obese and have increased food intake with altered pigmentation and adrenal insufficiency (8A ) (Fig. 2). Pomc–/– mice had a significantly higher amount of both fat and lean tissue than age-matched normal wild-type (WT) mice. Additionally, the basal metabolic rate (as measured by oxygen consumption) was reduced by 23% in Pomc–/– mice when corrected for body weight, and total plasma T4 levels were significantly lower than those of WT mice. These data demonstrate that the obesity phenotype seen in Pomc–/– mice may be the consequence of a reduced metabolic rate as well as increased food intake, although whether this is a consequence of an alteration in the hypothalamic-pituitary-thyroid axis remains to be determined.
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). At 6 months of age they weighed 20% more than WT littermates, whose weight remained unaffected by the high fat diet. This was the result of increased energy intake, with Pomc–/– and Pomc+/– eating 40% and 18% more than WT mice, respectively. The observation that haploinsufficiency of this gene interacting with a change in diet results in an obesity phenotype is pertinent given the evidence implicating the region of human chromosome 2 containing the POMC gene as a susceptibility locus for common human obesity (9). Mutations in PC-1.
In addition to their role in normal POMC processing, PC1 and PC2 play an important role in the posttranslational modification of several other hormone precursors, including proinsulin and proglucagon. We have previously reported a woman with severe early-onset obesity, hypogonadotropic hypogonadism, postprandial hypoglycemia, hypocortisolemia, and evidence of impaired processing of POMC and proinsulin (10). She is a compound heterozygote for PC1 mutations: Gly593Arg, which causes failure of maturation of the inactive propeptide form of PC1 (pro-PC1) and its retention in the endoplasmic reticulum, and A
C+4 in the donor splice site of intron 5, resulting in exon skipping, a frameshift, and a premature stop codon in the catalytic domain. The recent description of mice rendered null for PC1 by homologous recombination confirmed the features of PC1 deficiency first reported in humans, such as defective POMC and proinsulin processing (11). However, unlike humans, who have severe early-onset obesity and normal linear growth, PC1-null mice are not obese and are growth retarded. This has been attributed to impaired GHRH processing that results in low circulating GH levels; in contrast, serum IGF-I levels in humans with PC1 deficiency are normal. The absence of obesity in the PC1-null mouse is surprising given the severe abnormalities of POMC processing and the phenotype of Pomc-null mice outlined above. It is likely that the relative importance of PC1 for POMC processing may differ between humans and mice, with loss of PC1 function in humans having a more adverse effect on food intake and weight.
We have recently described the second case of congenital PC1 deficiency, in a patient who was a compound heterozygote for two loss of function mutations: Glu250stop, which is predicted to truncate the PC1 protein within the catalytic domain, and Ala213del, which deletes a highly conserved alanine residue near the catalytically essential His208 residue (12). Intriguingly, this patient suffered from severe small intestinal absorptive dysfunction as well as the characteristic severe early-onset obesity, impaired prohormone processing, and hypocortisolemia. We hypothesized that the small intestinal dysfunction seen in this patient and, to a lesser extent, in the first patient we described may be the result of a failure of maturation of propeptides within the enteroendocrine cells and nerves that express PC1 throughout the gut. The finding of elevated levels of progastrin and proglucagon provided in vivo evidence that, indeed, prohormone processing in enteroendocrine cells was abnormal. Glucagon-like peptide-2 (GLP-2), which is formed in the gut from proglucagon, was an obvious candidate for a role in the intestinal dysfunction, because it has trophic effects on small intestinal epithelium. However, direct plasma assays and chromatography/RIA showed that GLP-2 was still present in plasma despite complete loss of function mutations in PC1.
Interestingly, PC1-null mice also have a gastrointestinal phenotype (bulky moist stools), but in the mouse model, GLP-2 was undetectable in gut extracts (11). However, because plasma levels were not measured in the mouse and we could not study the human gut directly, the relationship between the murine and human findings remains unresolved, although it is very likely that in both species, small intestinal dysfunction results from disordered prohormone processing within enteroendocrine cells. It is possible that the relative importance of convertases, processing of gut neuropeptides and their functions differ between mice and humans, and that the gut dysfunction in humans relates to deficiency of peptides other than GLP-2. An important caveat regarding prohormone processing disorders is that it is very difficult to state with certainty which altered phenotypes are due to which altered processing events. This uncertainty derives from the fact that these enzymes act on multiple precursors, some of which may not yet be fully characterized.
We do not, as yet, have a complete picture of the series of molecular events leading to POMC processing, and this ignorance is reflected in some puzzling phenotypes in both mice and humans. The maturation of PC2 requires the aid of a helper protein, 7B2, to generate an enzymatically active form. Thus, PC2- and 7B2-null mice might be expected to exhibit similar defects in precursor processing. However, these two null mice are phenotypically very different (13, 14). PC2-null mice are glucagon deficient and become hypoglycemic, but have a normal life span with no major alterations in growth or weight despite lacking MSH (13). In contrast, 7B2-null mice have extremely elevated levels of ACTH and die of a syndrome of corticosterone excess (14). Interestingly, when 7B2-null mice are adrenalectomized, although they now avoid corticosterone excess, they develop a profound late-onset obesity (15). A further puzzle is provided by a child with early-onset obesity, adrenal insufficiency, and undetectable ACTH, but large amounts of circulating POMC (16). However, in this child proinsulin processing (by PC1 and PC2) is entirely normal, plasma POMC levels respond appropriately to CRH, and dexamethasone and the POMC genomic sequence are normal. The precise cause of this child’s POMC-specific processing defect remains obscure.
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Defects in the action of POMC-derived products |
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TopAbstractIntroductionDefects in the synthesis...Defects in the action...ConclusionsReferences |
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MSH at MC1R expressed on the surface of melanocytes. Agouti induces a switch in pigment production from brown-black eumelanin to yellow-red phaeomelanin. A number of dominant agouti alleles, such as Ay and Avy, result in widespread ectopic expression of the agouti protein, giving rise to a distinct neuroendocrine phenotype of obesity, hyperphagia, hyperinsulinemia, hyperglycemia in males, increased linear growth, and yellow coat color (2). The potential mechanism of how a peptide that regulates hair color could be linked to an obesity syndrome was made clearer when agouti was found to antagonize MC4R as well as MC1R. Additional insights came with the identification in rodents and humans of the hypothalamic neuropeptide, AGRP (17). AGRP is a melanocortin receptor antagonist, primarily at MC3R and MC4R, and shares high sequence homology with agouti. AGRP mRNA is expressed only in the arcuate nucleus and is significantly elevated in both ob/ob mice and fasted WT mice. Transgenic mice ubiquitously expressing human AGRP developed hyperphagia and an obesity phenotype indistinguishable from that of the agouti mouse without an effect on pigmentation (17). Thus, the obesity seen in the agouti mouse is as a result of aberrant antagonism of hypothalamic melanocortin receptors, and AGRP exerts it potent orexigenic effects by antagonizing MSH at central melanocortin receptors. Given its ability to increase food intake and cause obesity, mutations that either caused an up-regulation in AGRP expression or potentiated its melanocortin antagonist action could conceivably cause an obesity phenotype in humans. There are reports of single nucleotide polymorphisms in the both the promoter region and the coding region that are associated with obesity phenotypes (18).
MC4R knockout mice.
Using homologous recombination to delete the coding sequence of Mc4r, Huszar and colleagues generated a mouse that developed a maturity-onset obesity syndrome associated with increased food intake, hyperinsulinemia, and hyperglycemia (19). Mc4r–/– had similar basal corticosterone levels, but an increase in linear growth compared with WT. In addition, mice heterozygous for the Mc4r-null mutation had an intermediate phenotype between wild-type and Mc4r–/– for body weight, linear growth, and insulin, strongly suggestive of a gene dosage effect.
Since this initial report a number of studies have further examined the role of MC4R in metabolism. Using the technique of pair-feeding to investigate the contributions of factors other than increased food intake to the phenotype seen in Mc4r-null mice, Ste. Marie et al. demonstrated that Mc4r–/– females still became significantly heavier than WT littermates with the body weight difference accounted for by an elevation in fat pad weight (20). Measurements of metabolic rate in young animals of similar body weight demonstrated that Mc4r–/– animals consumed 20% less oxygen than same-weight WT mice, and the locomotor activity of young nonobese Mc4r–/– males was reduced compared with that of WT males. These data suggest that MC4R deficiency leads to defective regulation of energy expenditure, with Mc4r-null mice being more metabolically efficient than WT mice. Results from placing Mc4r–/– mice on a modified diet also strongly suggest that this receptor is necessary to effect appropriate changes in homeostatic mechanisms in response to a changes in the caloric content of diet (21). On a high fat diet, WT mice were transiently hyperphagic, but remained a normal weight because of an increase in diet-induced thermogenesis, a rapid correction of food intake back to an isocaloric level and an increase in spontaneous activity levels. In contrast, a high fat diet resulted in Mc4r–/– mice developing obesity at an accelerated rate due to sustained hyperphagia, a much reduced level of diet-induced thermogenesis and a lack of increase in motor activity.
Human MC4R deficiency.
In 1998, two groups reported heterozygous mutations in the MC4R in humans that were associated with dominantly inherited obesity (22, 23). Since then, heterozygous mutations in MC4R have been reported in obese humans from various ethnic groups and represent the commonest known monogenic cause of human obesity (5–6% in our cohort of severely obese subjects). Some studies have observed a lower prevalence, and this may be explained by the differing prevalence in certain ethnic groups, although it is more likely to reflect the later onset and reduced severity of obesity of the subjects in these studies. Taking account of all of these observations, codominance, with modulation of expressivity and penetrance of the phenotype, is the most appropriate descriptor for the mode of inheritance.
As well as the increase in fat mass, MC4R mutant subjects also have an increase in lean mass that is not seen in other monogenic obesity syndromes such as leptin deficiency (24). Affected children have increased linear growth with a height SD score of +2 compared with population standards (Fig. 3). MC4R-deficient subjects also have higher levels of fasting insulin than age, sex, and body mass index SD score-matched children (25). The accelerated linear growth and the disproportionate early hyperinsulinemia are consistent with observations in the Mc4r–/– mouse and other rodent models of impaired melanocortin signaling, such as agouti (2). In general, patients with MC4R mutations have free T4 concentrations in the lower end of the normal range with slightly elevated TSH concentrations suggestive of hypothalamic hypothyroidism (25).
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We have studied in detail the signaling properties of many of these mutant receptors, and this information should help to advance the understanding of structure/function relationships (26). Importantly, we have been unable to demonstrate evidence for dominant negativity associated with these mutants, which suggests that MC4R mutations are more likely to result in a phenotype through haploinsufficiency (26).
Role of the MC3R.
The data defining the physiological function of MC3R in energy metabolism are not of the same magnitude as those for MC4R. Nevertheless, two independent models of mice lacking a functional MC3R suggest that these two receptors serve nonredundant roles (27, 28). Both studies demonstrated that homozygous-null Mc3r (Mc3r–/–) mice have a unique phenotype, in that although they are not being significantly overweight, they have an increased fat mass and a reduction in lean mass compared with WT mice. Both groups also reported a reduction in the body length of Mc3r–/– mice. In addition, the study by Chen et al. (27) reported a number of sexually dimorphic features, with male Mc3r–/– mice displaying hypophagia and elevated insulin levels, whereas female Mc3r–/– mice had a trend to lower corticosterone levels with a significant difference in ambulatory activity. The report by Butler et al. (28) observed a significant increase in weight of female Mc3r–/– mice with an increase in respiratory quotient, suggestive of a reduced ratio of fat to carbohydrate oxidation on a high fat diet and, in contrast to the other model, noted a reduction in locomotor activity in male homozygous-null mice only.
Our current understanding of the role of MC3R is that it may influence feed efficiency and the partitioning of fuel stores into fat. The nonredundant function of MC3R and MC4R is illustrated by the finding that mice lacking both become heavier than mice lacking MC4R alone, with absent MC4R signaling causing hyperphagia and MC3R loss resulting in these ingested calories being efficiently stored as fat (27).
Direct sequencing of the MC3R gene-coding sequence in populations with type 2 diabetes mellitus and obesity has identified a number of sequence variants. However, these have all been detected in unaffected controls with similar frequencies or have been absent in family members who were also obese, and as yet there is no convincing evidence for a major role of MC3R mutations in causing a severe metabolic phenotype in humans (29).
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Conclusions |
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TopAbstractIntroductionDefects in the synthesis...Defects in the action...ConclusionsReferences |
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Footnotes |
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Abbreviations: AGRP, Agouti-related protein; GLP-2, glucagon-like peptide-2; MC3R, melanocortin receptor type 3; PC, prohormone convertase; POMC, proopiomelanocortin; WT, wild type.
Received March 2, 2004.
Accepted March 18, 2004.
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TopAbstractIntroductionDefects in the synthesis...Defects in the action...ConclusionsReferences |
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) compared with the hypothalamus (
).
) or high fat (