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The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 4 1442-1446
Copyright © 2001 by The Endocrine Society

Special Articles

Obesity as a Neuroendocrine Disease: Lessons to Be Learned from Proopiomelanocortin and Melanocortin Receptor Mutations in Mice and Men*

Sharon L. Wardlaw

Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032

Address correspondence and requests for reprints to: Dr. Sharon L. Wardlaw, Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032. E-mail: sw22{at}columbia.edu * Supported by NIH Grants


   Introduction
Top
 Introduction
POMC
 MC-Rs
 Central melanocortin system and...
 POMC and MC-R mutations...
 The melanocortin system as...
 Conclusions
 References
 
Proopiomelanocortin (POMC) is best known to the clinical endocrinologist as the precursor for pituitary ACTH, which is essential for maintaining adrenal cortical function. The most well recognized POMC deficiency syndrome is seen in patients with pituitary disease who fail to secrete ACTH normally and develop secondary adrenal insufficiency. These patients typically complain of anorexia and weight loss, which is corrected by glucocorticoid replacement. Recently, several cases of genetic POMC deficiency have been described, and in contrast to the usual hypopituitary patient with selective pituitary POMC deficiency, these individuals have increased appetite and are obese (1). A similar obesity syndrome has been described in transgenic mice with targeted deletion of the coding region of the Pomc gene (2). These POMC-deficient patients and mice are obese despite having profound secondary adrenal insufficiency. Thus, the effects on energy homeostasis are quite different with generalized POMC deficiency as opposed to the typical hypopituitary patient with POMC deficiency limited to the pituitary. A number of recent studies have established that POMC neurons in the hypothalamus are important regulators of energy homeostasis and that the POMC-derived peptide {alpha} melanocyte-stimulating hormone ({alpha}-MSH) and brain melanocortin receptors (MC-Rs) play a key role in this process. This short review focuses on the regulation of feeding behavior and body weight by the brain melanocortin neuropeptide system and the potential implications for the treatment of human obesity.


   POMC
Top
 Introduction
 POMC
MC-Rs
 Central melanocortin system and...
 POMC and MC-R mutations...
 The melanocortin system as...
 Conclusions
 References
 
Human POMC is a 267 amino acid precursor protein that is synthesized in the pituitary, in the arcuate nucleus of the hypothalamus, in the solitary tract of the medulla, and in several peripheral tissues. The posttranslational processing of POMC is tissue specific and results in the production of a number of peptides with very different biological activities (Refs. 3, 4, 5 ; Fig. 1Go). Functionally active peptides are produced by endoproteolytic cleavage at adjacent pairs of basic amino acids by the prohormone convertases PC1 and PC2 (6). In the anterior pituitary, POMC is processed predominantly to ACTH, which is critical for the maintenance of adrenocortical function, as well as to ß-lipotropin (LPH) and a 16-kDa N-terminal fragment. In the hypothalamus and in the intermediate lobe of the pituitary (which is prominent in the rodent), POMC is more extensively processed: ACTH is further processed to produce {alpha}-MSH and corticotropin-like intermediate lobe peptide; ß-LPH is processed to ß-endorphin and {gamma}-LPH; and N-terminal POMC is processed to {gamma}3-MSH. Within the brain, ß-endorphin and the MSH peptides have wide-ranging effects on neuroendocrine regulation, analgesia, behavior, and immune function. It is now clear that {alpha}-MSH and brain MC-Rs also play an important role in regulating feeding behavior and energy balance. The regulation of POMC gene expression and peptide release is tissue specific. In the anterior pituitary, POMC is stimulated by CRH and inhibited by glucocorticoids; in the intermediate lobe, POMC is regulated by dopamine. In the hypothalamus, a number of steroid hormones, neurotransmitters, and neuropeptides have been reported to affect Pomc gene expression or peptide release. These include sex steroids, glucocorticoids, opioids, dopamine, {gamma}-aminobutyric acid, CRH, and neuropeptide Y (NPY). It should be noted that the same treatment may have quite different effects on Pomc expression in the pituitary compared with the hypothalamus. For example, after adrenalectomy, Pomc gene expression is markedly up-regulated in the anterior pituitary but can be suppressed in the hypothalamus (7, 8). It has recently been shown that POMC neurons in the hypothalamus are important targets for leptin, a hormone secreted by fat cells, which plays a key role in communicating the levels of peripheral energy stores to the brain (Ref. 9 ; Fig. 2Go). There is accumulating evidence that {alpha}-MSH is one of the downstream mediators of the effects of leptin on energy homeostasis.



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  		Figure 1. Schematic diagram of the POMC precursor molecule and the major peptide products that are derived from this precursor by endoproteolytic cleavage. JP, Joining peptide; CLIP, corticotropin-like intermediate lobe peptide.

 


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  		Figure 2. Diagram depicting the effects of leptin on hypothalamic POMC and AGRP neurons and their interaction with hypothalamic MC-Rs. MC4-R signaling is stimulated by {alpha}-MSH and inhibited by AGRP. Leptin, which is secreted by fat cells, stimulates POMC and inhibits AGRP, thus increasing MC4-R signaling and inhibiting food intake. Leptin also inhibits NPY, which is synthesized in the same neurons as AGRP. Stimulatory interactions are shown in solid lines, and inhibitory interactions in dashed lines.

 

   MC-Rs
Top
 Introduction
 POMC
 MC-Rs
Central melanocortin system and...
 POMC and MC-R mutations...
 The melanocortin system as...
 Conclusions
 References
 
The biological effects of ACTH and the MSH peptides are mediated by interactions with specific G protein-coupled, seven-transmembrane receptors. Five MC-Rs have recently been cloned (Table 1Go). The MC1-R is expressed almost exclusively in melanocytes and mediates effects on skin pigmentation and coat color (10). Mutations of the Mc1-r gene are associated with alterations in coat color in animals. In the human, MC1-R gene sequence variants have been reported in over 80% of individuals with red hair and/or fair skin that tans poorly (11). The MC2-R is expressed primarily in the adrenal cortex and mediates the effects of ACTH on glucocorticoid synthesis and release. A number of patients with familial glucocorticoid deficiency have been shown to have mutations of the MC2-R gene (12). The MC3-R and MC4-R are both highly expressed in the brain and specifically in areas known to be involved in regulating energy balance. The MC3-R is localized to the hypothalamus and the limbic system and is highly expressed by arcuate neurons, including POMC neurons (13, 14). The MC4-R is more widely distributed throughout the brain, in the hypothalamus, thalamus, cortex and brain stem (15). Within the hypothalamus, the MC4-R is highly expressed in the paraventricular nucleus and the lateral hypothalamic area, which are both important in regulating energy balance. The MC5-R is expressed primarily in exocrine glands and in skeletal muscle (16). Mc5-r knockout mice have exocrine gland dysfunction and decreased production of sebaceous lipids. The MC-Rs can be activated by both ACTH and {alpha}-MSH, except for the MC2-R, which is activated primarily by ACTH. The MC3-R, unlike the other receptors, is also potently activated by {gamma}3-MSH. Disruption of the MC1-R, MC2-R, and MC5-R results in abnormalities of pigmentation, adrenal function, and exocrine gland function, respectively, but not in changes in energy homeostasis. In contrast, there is considerable evidence that the MC4-R plays an important role in energy homeostasis. As discussed below, targeted disruption of this receptor produces hyperphagia and obesity in transgenic mice (17), and MC4-R mutations have been found in obese humans. A role for the MC3-R in energy homeostasis is indicated by a recent study showing that disruption of the MC3-R results in increased fat mass and decreased lean body mass (18).


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  		Table 1. Melanocortin receptor family

 

   Central melanocortin system and mouse models of obesity
Top
 Introduction
 POMC
 MC-Rs
 Central melanocortin system and...
POMC and MC-R mutations...
 The melanocortin system as...
 Conclusions
 References
 
A number of studies have shown that intracerebroventricular injection of {alpha}-MSH and other synthetic MSH agonists can suppress food intake in the rodent and that this effect can be blocked by specific {alpha}-MSH antagonists (19, 20). Injection of SHU9119, a synthetic {alpha}-MSH antagonist, increases food intake, indicating a role for endogenous {alpha}-MSH in appetite control. Two naturally occurring MSH antagonists, agouti protein and agouti-related protein, have been identified that can stimulate food intake. Agouti is a 131-amino acid protein that is normally expressed within hair follicles and regulates the synthesis of pigments that produce coat color. Agouti antagonizes the effects of {alpha}-MSH at the MC1-R, which results in a lighter coat color. Naturally occurring mutations of the agouti locus such as the lethal yellow (Ay) cause widespread ectopic expression of agouti. These animals have a yellow coat color and develop hyperphagia, hyperinsulinemia, obesity, and increased body length. The obesity results from antagonism of the MC4-R due to ectopic expression of agouti within the brain. A similar obesity syndrome is produced by targeted disruption of the MC4-R (17). These mice develop a maturity onset obesity syndrome characterized by hyperphagia, hyperinsulinemia, hyperglycemia, and increased body length. Mice heterozygous for the Mc4-r deletion exhibit a phenotype intermediate between that of the wild-type and homozygous littermates. Mc3-r knockout mice have increased fat mass and reduced lean body mass but are not hyperphagic (18). When exposed to a high-fat diet, these mice eat normal amounts of food but gain more weight than wild-type mice, consistent with increased feed efficiency. Mice lacking both the Mc3-r and the Mc4-r weigh significantly more than mice lacking only the Mc4-r. Thus, both receptors regulate energy balance in a nonredundant manner.

An endogenous melanocortin antagonist, agouti-related protein (AGRP), has now been identified in the hypothalamus (21, 22). AGRP is a 132-amino acid peptide that is synthesized in the arcuate nucleus and is structurally homologous to the agouti protein. Within the arcuate nucleus, AGRP and POMC are expressed by separate neuronal populations. AGRP is a potent MC3-R and MC4-R antagonist that, when overexpressed in transgenic mice, causes hyperphagia and obesity. When injected intracerebroventricularly, AGRP is a potent orexigenic agent (23). There is almost complete coexpression of AGRP with another orexigenic peptide, NPY, in arcuate neurons (24). AGRP and NPY fiber tracts originate in the arcuate and project to other hypothalamic and brain regions (24, 25). Fibers immunoreactive for {alpha}-MSH form a population separate from AGRP fibers, but their terminals are intermingled. It is believed that the projections of these POMC and AGRP/NPY neurons to the paraventricular nucleus and the lateral hypothalamic area are particularly important in regulating feeding behavior (26, 27). Interactions between AGRP and {alpha}-MSH at the MC4-R in these hypothalamic regions seems to be critical in maintaining energy homeostasis. Leptin receptor messenger RNA (mRNA) and protein is highly expressed in both POMC and AGRP neurons, and leptin seems to regulate Pomc and Agrp expression in a reciprocal manner (9, 26, 28). POMC mRNA levels in the hypothalamus are low, and AGRP levels are increased during fasting when leptin is suppressed (29, 30, 31). Obese leptin-deficient mice (ob/ob) and leptin receptor-deficient mice (db/db) have decreased POMC and increased AGRP mRNA levels in the hypothalamus, which in the ob/ob mice are restored to normal by leptin injection (31, 32, 33, 34, 35). Intracerebroventricular injection of leptin has also been shown to stimulate POMC mRNA levels and to suppress AGRP levels in food-deprived rats (33, 36, 37, 38). Thus, leptin can regulate MC4-R signaling by both increasing levels of the agonist, {alpha}-MSH, and decreasing levels of the antagonist, AGRP (Fig. 2Go).

Recently, a POMC-null mutant mouse strain was created (2). The entire third exon of Pomc was deleted, thus removing the coding region for all of the POMC-derived peptides. Homozygous Pomc knockout mice have defective adrenal development, altered pigmentation, and develop obesity. No macroscopically discernible adrenal glands were found in these animals, but on microscopic examination some evidence of rudimentary adrenal cortex or medulla was reported. Serum levels of corticosterone and aldosterone were undetectable in the mutant mice, and plasma epinephrine levels were also markedly reduced compared with the wild-type mice. Thus, POMC-derived peptides seem to be critical not only for steroidogenesis but also for normal adrenal development. Although glucocorticoids are known to be necessary for normal lung development and for production of surfactant proteins, no lung abnormalities were noted in the initial description of the Pomc knockout mice. Glucocorticoid receptor-deficient mice die shortly after birth with lung atelectasis (39). In contrast, homozygous CRH knockout mice, which are also glucocorticoid deficient, survive unless the mother is also CRH and glucocorticoid deficient (40), indicating that placental transfer of maternal glucocorticoids can compensate for the fetal glucocorticoid deficiency. It is likely that the Pomc knockout mice will have similar pulmonary abnormalities if deprived of maternal glucocorticoids.

Despite the lack of corticosteroids, the homozygous Pomc mutant mice develop hyperphagia and obesity. Increased weight gain was noted in the second postnatal month, and by the third postnatal month weights were about twice those of the wild-type mice. There was also a significant increase in body length, as was reported for Mc4-r knockout mice. Serum leptin levels were markedly increased in homozygous Pomc mutant mice. Interestingly, leptin levels were also increased in heterozygous mutant mice although body weight was normal. When homozygous Pomc mutant mice were treated with daily ip injections of a synthetic {alpha}-MSH agonist, there was a significant decrease in food intake and substantial weight loss. After 2 weeks of treatment, the mutant mice had lost 46% of their excess body weight; there was no weight loss in the similarly treated wild-type littermates. When the {alpha}-MSH agonist injections were stopped, the mutant mice returned to their pretreatment weight. The effectiveness of {alpha}-MSH injection in this model makes the development of {alpha}-MSH agonists an attractive therapeutic target, especially because, as described below, genetic defects in both POMC and the MC4-R have now been described in human obesity.


   POMC and MC-R mutations and human obesity
Top
 Introduction
 POMC
 MC-Rs
 Central melanocortin system and...
 POMC and MC-R mutations...
The melanocortin system as...
 Conclusions
 References
 
Recently, Krude et al. (1) reported two patients from Germany with genetic POMC deficiency characterized by adrenal insufficiency, red hair pigmentation, and early-onset obesity. The first patient was found to be a compound heterozygote for two mutations in exon 3 that resulted in ACTH and {alpha}-MSH deficiency. She had a normal birth weight and was diagnosed with adrenal insufficiency when she developed cholestasis at 3 weeks of age and was treated with hydrocortisone replacement. Increased appetite and obesity was first noted at 4 months of age. The second patient was homozygous for a mutation in exon 2, which abolishes POMC translation. His birth weight was normal, and obesity was first noted at 5 months of age. Adrenal insufficiency was diagnosed at 12 months of age when he developed hypoglycemia and hyponatremia and was treated with hydrocortisone replacement. Subsequent development in both children was normal, except for the abnormal eating behavior and obesity. Both children had pale skin and red to red-orange hair color. The heterozygous parents in both families had normal adrenal function and did not have obesity or red hair. More recently, two other pediatric patients were described with a similar POMC deficiency syndrome (41). A 4-yr-old boy from Slovenia was found to be a compound heterozygote for two new POMC mutations, and a boy from The Netherlands was found to have the same previously described POMC exon 2 mutation. Impaired processing of POMC has also been associated with human obesity in two instances. In one patient the processing abnormality was due to mutations in the prohormone convertase 1 gene (42); in the second patient the cause remains obscure (43). Further evidence that POMC may modulate weight level in humans is provided by a study in a population of Mexican Americans showing a linkage of serum leptin levels and fat mass to an interval on chromosome 2, which includes the POMC locus (44). Subsequent studies in a French and in an African-American population have reported similar associations (45, 46).

In contrast to POMC mutations, which are a relatively rare cause of human obesity, MC4-R mutations are more commonly associated with morbid obesity. A number of studies have now reported heterozygous mutations in the human MC4-R gene that are associated with obesity in a dominant fashion. Vaisse et al. (47) screened 209 morbidly obese patients and found that 4% had heterozygous MC4-R mutations; no such mutations were found in controls. Farooqi et al. (48) screened 243 subjects with severe, early-onset obesity and found that 3.3% had potentially pathogenic MC4-R mutations. The majority of subjects reported, to date, with null alleles of the MC4-R or missense mutations that alter MC4-R function have been obese. However, some patients with these mutations are not obese. It, thus, seems that haploinsufficiency mutations in the MC4-R gene cause obesity with variable expressivity. Farooqi et al. (48) report that affected children were hyperphagic and had increased growth velocity. A marked increase in bone mineral density was also seen in all affected subjects in that study. The thyroid, adrenal, and reproductive axes were reported to be normal in these patients. Thus, the human phenotype caused by impaired MC4-R function seems to resemble that reported previously in the Mc4-r knockout mouse.


   The melanocortin system as a potential target for the treatment of obesity
Top
 Introduction
 POMC
 MC-Rs
 Central melanocortin system and...
 POMC and MC-R mutations...
 The melanocortin system as...
Conclusions
 References
 
The studies described above clearly indicate an important role for the central melanocortin system in maintaining energy balance and have potential therapeutic implications for human obesity. An important consideration in developing effective {alpha}-MSH agonists is that the potential compounds cross the blood-brain barrier and gain access to the appropriate hypothalamic MC-Rs. A number of animal studies have demonstrated inhibitory effects of either native {alpha}-MSH or of {alpha}-MSH analogs on feeding behavior (20, 49). In most of these studies, however, peptides were administered directly into the brain by the intracerebroventricular route. Peripheral administration of an {alpha}-MSH analog was effective, however, in the Pomc knockout mouse (2). MSH analogs have been administered to a small number of human subjects to evaluate effects on skin tanning and on erectile function. Both [Nle4, DPhe7] {alpha}-MSH, referred to as melanotan (MT)-I, and Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2, referred to as MT-II, have been shown to be effective in promoting tanning when given sc for several weeks (50, 51). MT-II was also noted to produce penile erections in normal men and in men with psychogenic erectile dysfunction (52). Side effects noted in these studies included flushing, nausea, anorexia, gastrointestinal discomfort, and fatigue. Although these analogs are likely acting on the MC1-R in the skin to produce tanning, the exact locus of action of the other reported effects is still unknown. The challenge will be to develop stable, well-tolerated {alpha}-MSH analogs that gain access to central MC-Rs. Other approaches might include compounds that stimulate hypothalamic POMC synthesis and increase {alpha}-MSH release or inhibit AGRP synthesis and release. There is still much to be learned about the downstream effects of MC-R activation and how the melanocortin pathway interacts with other central and peripheral regulators of energy homeostasis (53).


   Conclusions
Top
 Introduction
 POMC
 MC-Rs
 Central melanocortin system and...
 POMC and MC-R mutations...
 The melanocortin system as...
 Conclusions
References
 
The central melanocortin system, which consists of POMC, AGRP, and the brain MC-Rs, plays a key role in regulating feeding behavior and energy homeostasis. A growing number of studies in both the mouse and the human with genetic defects in the synthesis or processing of POMC, or with defects in MC-R signaling, clearly indicate the importance of this system. A genetic POMC deficiency syndrome characterized by adrenal insufficiency, red hair pigmentation, and early-onset obesity has recently been described in the human. It is particularly striking that obesity occurs in patients with generalized POMC deficiency and in Pomc knockout mice despite the presence of adrenal insufficiency. The contrast between these patients with generalized POMC deficiency and with the more typical patients who have POMC deficiency limited to the pituitary underscores the critical role that hypothalamic POMC plays in regulating energy balance. The importance of the MC4-R in this process is demonstrated by the Mc4-r knockout mouse and by the growing number of obese patients reported with MC4-R mutations, making this the most common known monogenic cause of human obesity. The melanocortin regulatory system seems to be sensitive to variations in MC4-R expression, as indicated by the fact that heterozygous mutations produce obesity in both mice and in humans. Thus, there is considerable evidence that the hypothalamic melanocortin pathway regulates human feeding behavior and energy homeostasis and that abnormalities in this pathway can lead to obesity. A more detailed understanding of the control of this pathway and its integration with a growing number of other hypothalamic signaling pathways involved in maintaining energy balance will hopefully lead to effective new therapies for human obesity.

Received September 7, 2000.

Revised November 3, 2000.

Accepted November 10, 2000.


   References
Top
 Introduction
 POMC
 MC-Rs
 Central melanocortin system and...
 POMC and MC-R mutations...
 The melanocortin system as...
 Conclusions
 References
 

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