Where is pomc located

Peptides : neuropeptides. Endomorphin-1 Endomorphin Met-enkephalin Leu-enkephalin. See here instead. Antagonists: Nastorazepide.

Propeptides: Preproglucagon Proglucagon. Agonists: Kisspeptin Kisspeptin Antagonists: Kisspeptin Agonists: Leptin Metreleptin. Agonists: Melanin concentrating hormone. Agonists: Insulin-like factor 3 Relaxin 1 , 2 , 3 Serelaxin. Agonists: Thyrotropin alfa TSH thyrotropin. Categories : Genes on human chromosome Protein pages needing a picture All articles with unsourced statements Articles with unsourced statements from December Articles with invalid date parameter in template Wikipedia articles incorporating text from the United States National Library of Medicine Neuropeptides Neuroendocrinology Precursor proteins.

Cookies help us deliver our services. By using our services, you agree to our use of cookies. Namespaces Home Page Discussion. Views Read View source View history Help. AgRP, its interactions with the melanocortin system and other roles has been well reviewed recently [ 70 ]. However, mc4r ko, pomc ko and normal mice have similar anorexia with PYY, suggesting it can act independently of melanocortins too [ 9 , 82 ].

Lethal yellow is an inbred obese mouse strain, resulting from overexpression of agouti, which then has excess AgRP-like actions in the CNS [ 69 ]. Arcuate nucleus vgf mRNA expression is increased in hamsters in experimental short photoperiod situations mimicking winter, suggesting a feeding-related hibernation function for VGF [ 84 ]. Galanin blocks arcuate neuronal firing in those neurones expressing gal-r1 receptor mRNA, perhaps via direct contact with arcuate nucleus POMC neurones [ 87 ].

Vagotomy results in a slight reduction in food intake, but no change in body weight. LEPRB is found in several brainstem nuclei involved in the control of food intake, such as the DMX, area postrema, NTS, parabrachial, hypoglossal, trigeminal, lateral reticular and cochlear nuclei, locus coeruleus and inferior olive [ 94 ].

This suggests that the brainstem neurones are just as effective at mediating anorexia as the hypothalamic neurones and, like POMC, are direct targets for the action of leptin in the control of energy homeostasis [ 94 ].

However, part of this effect may be being mediated by hypothalamic arcuate nucleus POMC cells, as retrograde tracing experiments showed that a small percentage of these hypothalamic neurones project to the dorsal vagal complex [ 91 ]. Recently, leptin has been shown to modulate taste sensation directly, via the taste receptors, as well as via the brainstem [ 96 ].

Leptin could have a refining influence on feeding, via its actions on taste receptors and brainstem nuclei, but this is unlikely to involve brainstem POMC neurones in the process. The evidence, either genetic or neuropharmacological, for the key role of MC4R in feeding and the pathogenesis of obesity is as follows. The most common monogenic forms of human obesity are MC4R mutations [ 7 ]. Murine and human MC4R homozygous mutants are obese and hyperphagic [ 97 — ].

Murine and human MC4R heterozygous mutants are obese to a lesser extent. This shows sensitivity to quantitative variation in MC4R expression [ 97 , ], with mechanisms such as poor cell-surface expression or intracellular retention of the mutant receptors [ , ]. It is also possible that genetic defects in the intracellular trafficking mechanisms, required to present MC4R on the cell surface, could also lead to human obesity [ ].

Interestingly, human MC4R gene variants have also been associated with a lack of physical activity [ ]. The obesity of the lethal yellow and viable yellow strains of mice is due to over-expressed agouti with AgRP-like actions in the hypothalamus, having an antagonistic effect at the MC3R and MC4R receptor [ ].

MC4R agonists reduce feeding in rodents, with antagonists having the opposite effect [ , ]. Finally, MC4R agonists administered intranasally decrease bodyweight in humans [ ].

Perhaps the MC4R receptor does integrate the anorexigenic signal from leptin via the POMC neurones of the arcuate nucleus and brainstem. However, it is unlikely to be the only pathway. Similarly one can review the evidence, either genetic or neuropharmacological, for the function of MC3R in the pathogenesis of obesity. However, mice lacking both mc3r and mc4r are more obese than mc4r ko mice alone [ , ]. Also, the obesity of mc3r ko mice is more dependent on fat intake than that of the mc4r ko mice [ ].

Diet induced obesity in these two ko strains affects insulin-sensitivity more adversely in the mc4r ko mice [ ]. MC3R gene variants are common in humans, but they are not associated with obesity [ ]. While leptin administration reduces food intake in mc4r ko mice, mc3r ko mice do not show an anorexic response to leptin.

However, it should be noted that MC4R is found on the arcuate nucleus too [ 90 , ]. There are intra-arcuate POMC connections, suggesting that MC3R may mediate an autofeedback mechanism in the arcuate nucleus Tables 1 and 3 ; [ 61 , , ]. Administration of a specific MC3R agonist reduces the frequency of action potentials in POMC-containing neurones in the arcuate nucleus, which supports this hypothesis [ 62 ]. It is not yet known if any of these observations are important with regard to feeding behaviour, but they may be important with regard to overall control of POMC neural projections.

One impediment to comparative studies of melanocortin function is that it is very difficult to distinguish between the MSHs by immunocytochemistry, because of their similarity in core structure. Also, POMC neurones may release more than one peptide at any given synapse [ 42 ]. Whilst not being shown to activate hypothalamic neurones in vivo [ 42 ], it binds to and activates both MC3R and MC4R in vitro and has an anorectic effect at high doses in vivo [ ].

This has not yet, however, been demonstrated. It should be noted that binding of a ligand to a receptor does not necessarily correlate with biological activation of the cell expressing the receptor. Opioid antagonists block NPY induced feeding [ ]. Thus, there may be a more complementary interaction between the various POMC peptides in the regulation of feeding [ ]. Immunocytochemistry has been used to show that there are synaptic connections between POMC and enkephalin neurones in the arcuate nucleus [ ].

Using techniques already described in this article, the nucleus accumbens has been shown to have a POMC projection from the arcuate nucleus Table 1 ; [ 93 ]. It also contains endogenous opioids which mediate the positive emotional response to palatable foods such as sugar and fat. This may be their main role in appetite control, as opioid-evoked feeding is generally short lived [ ].

The PVN has both neuroendocrine and feeding roles. It has two major subdivisions, magnocellular and parvocellular, that fan either side of the roof of the 3rd ventricle. Surgical disruption of this pathway leads to obesity [ 58 ]. Activation of MC4Rs decreases body fat stores by reducing food intake and increasing energy expenditure. To identify which sites of mc4r expression are most relevant for mediating these effects, mice were generated with a loxP-modified, null mc4r allele loxTB mc4r that can be reactivated by Cre-recombinase [ ].

Notably, increased food intake was completely rescued while reduced energy expenditure was unaffected. Nesfatin-1 concentrations are reduced in the PVN with fasting. Also, the satiety effect of nesfatin-1 is not altered in Zucker rats with an leprb mutation and prior administration of an anti-nesfatin-1 antibody does not block leptin-induced anorexia.

This implies that leptin signalling is independent of nesfatin-1 signalling. These observations suggest that nesfatin-1 signalling is involved in a leptin-independent melanocortin signalling pathway in the hypothalamus. It is clear that the arcuate nucleus to PVN circuit is fundamental in the transmission of the satiety message in the hypothalamus. This suggests that CRF acts downstream of the melanocortin system.

These central effects of the melanocortins on the stress and thyroid axes suggest that POMC neurones may influence peripheral metabolism, which will in turn indirectly affect feeding behaviour. Damage to the lateral hypothalamus inhibits feeding, reducing body weight [ ]. The lateral hypothalamus expresses leprb mRNA and is regulated by leptin throughout development [ ].

However, both mc3r and mc4r mRNA are located in the lateral hypothalamus Table 3 ; [ 90 , ] and there is immunoreactive evidence of both POMC and AGRP fibres projecting from the arcuate nucleus to the lateral hypothalamus Table 1 ; [ 93 ] , so the lack of response to the MSHs administered icv is perhaps surprising.

Orexin expressing cells are located in the lateral, dorsal and perifornical nuclei. They innervate the arcuate nucleus, preoptic area, paraventricular nucleus of the thalamus, septal nuclei, locus coeruleus and DMX in the brainstem, as measured immunocytochemically.

Microinjection of orexins into the arcuate nucleus, PVN and lateral hypothalamus stimulates feeding [ — ]. It is possible to measure the action potential of individual living arcuate POMC neurones in mouse brain slices, identified by GFP transgenic tagging. Using whole cell patch clamp recordings, orexin suppresses the spontaneous firing in these neurones, suggesting that its appetite enhancing effects include an effect in suppressing hypothalamic POMC neuronal activity [ ]. Lesioning experiments suggest that it has extensive projections to the PVN, particularly portions involved in autonomic control [ ].

These experiments also show that lesions of this nucleus produce hypophagia and reduce linear growth [ ]. Using techniques already described in this article, there is evidence of POMC projections from the arcuate nucleus to the DMH Table 1 ; [ 93 ] and both mc3r and mc4r mRNA are found in this nucleus Table 3 ; [ 90 , ].

Using a retrograde-labelled approach to measure axonal transport, there is evidence that some of these projections from the DMH to the PVN may be under the control of POMC neurones originating in the arcuate nucleus [ ]. The SON lies laterally in a bilateral position at the base of the hypothalamus. The SON and the mPVN contain oxytocin and vasopressin cells, which project to the posterior pituitary, where these hormones are released [ 3 , ].

CCK co-expression in oxytocin neurones in the SON occurs in rats on a normal diet only, rather than a high fat diet [ ]. The VMH has no known neuroendocrine projections [ 42 ], but lesioning experiments show that it is involved in feeding behaviour in the rat [ ]. The projection from the arcuate nucleus to the VMH is very sparse and very few of these fibres are POMC neurones on immunocytochemistry Table 1 ; [ 93 ]. Despite this, mc3r and mc4r mRNA are abundant Table 3 ; [ 90 , ].

TrkB -deficient humans show learning difficulties and severe obesity [ ]. Similar observations were reported by others in a wide variety of ACTH-secreting extrapituitary tumors Steenbergh et al.

The underlying reasons for this observation have never really been fully elucidated. The cloning of the POMC gene provided a unique insight into the structural nature of the peptide. However, as technology developed it became obvious that potentially great insights into the function of POMC and its derived peptides might be obtained by deleting this gene in the mouse.

By chance, a naturally occurring POMC gene defect was identified in the human at approximately the same time. This review discusses the mouse models before turning to the human defects as the former provides a valuable model for the latter.

The mechanism for this is not clear. However, mice were shown to lose the opioid-dependent analgesia that could be induced by a swim test, but developed greater nonopioid analgesic mechanisms, presumably as a compensatory mechanism. There have been two independent strategies used to target the murine Pomc gene, which have provided broadly similar results Fig. There are, however, some subtle and potentially instructive distinctions between these different experiments.

Mouse Pomc deletion strategies. A shows the normal 3 exon structure of Pomc. B Yaswen etal. The translation product would therefore include the first 44 codons encoded on exon 2 followed by the neomycin resistance gene. Grey boxes represent the inserted homologous sequences. C Challis etal. Yaswen et al. Challis et al. The presence of the Lox P sites allowed the option for generation of conditional Pomc mutants in future studies. In addition, the exon 2 initiator methionine was mutated so that the N-terminal signal sequence and the 18 POMC amino acid residues encoded by this exon could not be produced — a theoretical disadvantage with the previous approach.

The advantage of this model is that this mouse strain is more inbred and hence more genetically homogeneous than the mouse and it also has a predisposition to diet-induced obesity. These models are summarised in Table 1. Summary of various mouse POMC gene deletion models and their key phenotypic characteristics. All groups reported that surviving mice were indistinguishable from wild-type littermates until the second month of life when it became apparent that they were becoming obese.

Substantial weight gain persisted and was accompanied by a small increase in body length. Furthermore, weight gain when placed on a high-fat diet was significantly greater than in wild-type animals. Mice were significantly hyperphagic and had reduced oxygen consumption, when corrected for body mass. Interestingly, heterozygous animals exhibit a very similar phenotype to wild types when raised on standard lab chow.

Circulating insulin is unchanged Hochgeschwender et al. Smart et al. However, despite this, animals develop adrenocortical hyperplasia with excess basal corticosterone, but reduced stress-induced corticosterone. Mice were shown to express excessive hypothalamic corticotrophin-releasing hormone CRH , implying that Pomc expression in the brain has a regulatory role on CRH expression. Furthermore, they are severely obese, hyperphagic, hyperleptinemic, and insulin resistant, reflecting the increased orexogenic effects of hypothalamic Pomc deficiency when normal or excessive glucocorticoid is available.

Bumaschny et al. They showed convincing data of a reversal of the obesity, hyperphagia, and insulin resistance of these animals when Pomc was reintroduced. This effect lessened with age so that the effect was only partial when Pomc reintroduction occurred at 6 months.

This same group subsequently used a leptin receptor-driven Cre recombinase to demonstrate that Pomc expression was only required in the leptin receptor-positive neurons of the hypothalamus for complete rescue of the obesity phenotype to be observed Lam et al. Slominski et al. Deletion of Pomc and the consequent ACTH deficiency is likely to lead to adrenal insufficiency with undetectable corticosterone. Heterozygous animals had near-normal corticosterone but, surprisingly, significantly reduced aldosterone.

Corticosterone was undetectable and remained so, even after receiving ACTH for 2 weeks. Microscopically, these adrenals had a distinguishable medulla and cortex, though further cortical zonation was not evident.

Treatment of these mice for 10 days with subcutaneous depot ACTH resulted in a recovery of adrenal weight to normal levels and the appearance of normal cortical zonation.

However, corticosterone was only minimally increased, and aldosterone was unchanged Coll et al. Heterozygous animals had significantly reduced corticosterone levels when compared with wild types. Further light was thrown on the adrenal discrepancies between these models by Karpac et al.

Soon after birth, however, adrenals failed to grow in knockout animals, and by 6 months of age were undetectable — as was reported by Yaswen et al. Although POMC has been shown to be an adrenal mitogen in a number of in vivo and in vitro experimental studies in rats Estivariz et al. Coll et al. These tumors showed reticulin breakdown and increased numbers of mitotic figures typical of adenoma formation. Tumor formation seems to correlate well with increased hypothalamic CRH mRNA in these animals, although a contribution from absent glucocorticoid feedback may also be important.

The first description of a human POMC defect in fact preceded the publication of the Pomc deleted mouse, and the clinical features accurately anticipated those that were later described in the mouse. Krude et al. They investigated this possibility in two unrelated children with precisely this syndrome and identified mutations in POMC. In their first patient, whose older brother had died at 7 months of age, adrenal hypoplasia had been identified and glucocorticoid replacement was started during the neonatal period.

Excessive weight gain became apparent from about 3 months of age as was red hair and a pale skin. Their second patient, identified at age 5, had an almost identical syndrome. POMC sequencing revealed a novel type of homozygous mutation that created a new initiator methionine just upstream of the conventional site, which resulted in a short, out-of-frame translation product that prevents translation from the correct site.

This would result in complete absence of any POMC peptide. These gene mutations lead to production of an abnormally short version of the POMC protein or no protein at all.

Loss of these peptides prevents signaling through their receptor proteins and disrupts certain functions in the body. Without ACTH, there is a reduction in cortisol production, which leads to low blood sugar hypoglycemia and other problems in affected individuals.

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