Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A growing body of evidence indicates that a number of peptides expressed in the mammalian hypothalamus are involved in the regulation of food intake and energy balance. Among these, melanin-concentrating hormone (MCH) and neuropeptide Y (NPY) are potent appetite stimulants, whereas alpha-melanocyte-stimulating hormone (alpha-MSH), neurotensin, and glucagon-like peptide (GLP)-1(7-36) amide have appetite-suppressing properties. However, the functional interactions between pathways involving these neuropeptides remain incompletely understood. In the current study, we describe the functional interactions between orexigenic (appetite-stimulating: MCH and NPY) and anorectic (appetite-suppressing: alpha-MSH, neurotensin, and GLP-1) peptides after intracerebroventricular (i.c.v.) administration in the rat. The i.c.v. administration of GLP-1 completely prevents the orexigenic effects of both MCH and NPY. However, i.c.v. administration of alpha-MSH prevents only the orexigenic effect of MCH, as we have previously shown, but does not prevent the effect of NPY on food intake. Similarly, i.c.v. administration of neurotensin prevents only the orexigenic effect of MCH, but does not prevent the appetite-stimulating effect of NPY. Thus, our study suggests that the functional interactions between these neuropeptides are specific, although the underlying mechanisms are as yet unexplored.
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PMID:Functional interactions between melanin-concentrating hormone, neuropeptide Y, and anorectic neuropeptides in the rat hypothalamus. 979 36

The possibility of developmental effects of POMC-derived melanocortins and analogs on neurons of fetal rat brain regions exhibiting marked developmental melanocortin receptor expression, was studied in serum-free co-cultures of gestational day 18 striatal and mesencephalic cells, and compared with NEI and NGE. These two peptide fragments of the melanin concentrating hormone precursor, occurring in brain areas devoid of POMC terminals, cross-react with alpha-MSH antibodies; NEI elicits grooming similar to alpha-MSH. Neurofilament protein (NF), growth-associated protein (GAP-43) and synaptophysin of the synaptosomal fraction were determined by ELISA as markers for neuritogenesis, growth cones, and nerve terminal differentiation. Cell survival was analyzed by MTT assay, proportions of major cell types by immunocytochemistry. alpha-Melanocyte-stimulating hormone (alpha-MSH, effective concentration 250-2500 nM), the analog Nle4-, D-Phe7-alpha-MSH (NDP, 3.1-750 nM), and NEI (250 nM) increased NF in 3 day cultures by 11%, 17%, and 22%, respectively, whereas ACTH(1-24) and ACTH(1-39) (25 2500 nM) were ineffective. In 11 day cultures, alpha-MSH (250-750 nM), but not NDP, ACTH(1-24) or ACTH(1-39), increased synaptosomal synaptophysin by 11%. GAP-43 and cell survival remained unaffected. These data indicate that selected melanocortins as well as NEI can influence differentiation of neural processes in brain neurons.
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PMID:Melanocortin and MCH precursor-derived NEI effects on striatum-midbrain co-cultures. 980 45

Feeding is influenced by hypothalamic neuropeptides that promote (orexigenic peptides) or inhibit feeding. Of these, neuropeptide Y (NPY) in the arcuate nucleus and melanin-concentrating hormone (MCH) and orexins/hypocretins in the lateral hypothalamus have received attention because their expression is increased during fasting and because they promote feeding when administered centrally. Surprisingly, absence of the orexigenic neuropeptide NPY fails to alter feeding or body weight in normal mice. As deficiency of a single component of the pathway that limits food intake (such as leptin or receptors for melanocortin-4) causes obesity, it has been suggested that orexigenic signals are more redundant than those limiting food intake. To define further the physiological role of MCH and to test the redundancy of orexigenic signals, we generated mice carrying a targeted deletion of the MCH gene. MCH-deficient mice have reduced body weight and leanness due to hypophagia (reduced feeding) and an inappropriately increased metabolic rate, despite their reduced amounts of both leptin and arcuate nucleus pro-opiomelanocortin messenger RNA. Our results show that MCH is a critical regulator of feeding and energy balance which acts downstream of leptin and the melanocortin system, and that deletion of a gene encoding a single orexigenic peptide can result in leanness.
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PMID:Mice lacking melanin-concentrating hormone are hypophagic and lean. 987 14

The novel neuropeptide cocaine-amphetamine-regulated transcript (CART) is expressed in several hypothalamic regions and has recently been shown to be involved in the central control of food intake. To characterize the hypothalamic CART neurons and understand the physiological functions they might serve, we undertook an in situ hybridization and immunohistochemical study to examine distribution and neurochemical phenotype of these neurons. In situ hybridization studies showed abundant CART mRNA in the periventricular nucleus (PeV), the paraventricular nucleus of the hypothalamus (PVN), the supraoptic nucleus (SON), the arcuate nucleus (Arc), the zona incerta, and the lateral hypothalamic area. The distribution of CART-immunoreactive neurons as revealed by a monoclonal antibody raised against CART(41-89) displayed complete overlap with CART mRNA. Double immunohistochemistry showed co-existence of CART immunoreactivity (CART-IR) and somatostatin in some neurons of the PeV. In the magnocellular division of the PVN as well as the SON, CART-IR was demonstrated in both oxytocinergic and vasopressinergic perikarya. In the medial parvicellular region of the PVN a few CART-IR neurons co-localized galanin, but none was found to co-localize corticotropin-releasing hormone. In the Arc, almost all pro-opiomelanocortinergic neurons were shown to contain CART, whereas no co-localization of CART with NPY was found. In the lateral hypothalamic area nearly all CART neurons were found to contain melanin-concentrating hormone. The present data support a role for CART in neuroendocrine regulation. Most interestingly, CART is co-stored with neurotransmitters having both positive (melanin-concentrating hormone) as well as a negative (pro-opiomelanocortin) effect on food intake and energy balance.
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PMID:Neurochemical characterization of hypothalamic cocaine- amphetamine-regulated transcript neurons. 1023 51

A photoreactive analogue of human melanin-concentrating hormone was designed, [D-Bpa13,Tyr19-MCH, containing the D-enantiomer of photolabile p-benzoylphenylalanine (Bpa) in position 13 and tyrosine for radioiodination in position 19. The linear peptide was synthesized by the continuous-flow solid-phase methodology using Fmoc-strategy and PEG-PS resins, purified to homogeneity and cyclized by iodine oxidation. Radioiodination of [D-Bpa13,Tyr19]-MCH at its Tyr19 residue was carried out enzymatically using solid-phase bound glucose oxidase/lactoperoxidase, followed by purification on a reversed-phase mini-column and HPLC. Saturation binding analysis of [125I]-[D-Bpa13,Tyr19]-MCH with G4F-7 mouse melanoma cells gave a K(D) of 2.2+/-0.2 x 10(-10) mol/l and a B(max) of 1047+/-50 receptors/cell. Competition binding analysis showed that MCH and rANF(1-28) displace [125I]-[D-Bpa13,Tyr19]-MCH from the MCH binding sites on G4F-7 cells whereas alpha-MSH has no effect. Receptor crosslinking by UV-irradiation of G4F-7 cells in the presence of [125I]-[D-Bpa13,Tyr19]-MCH followed by SDS-polyacrylamide gel electrophoresis and autoradiography yielded a band of 45-50 kDa. Identical crosslinked bands were also detected in B16-F1 and G4F mouse melanoma cells, in RE and D10 human melanoma cells as well as in COS-7 cells. Weak staining was found in rat PC12 phaeochromocytoma and Chinese hamster ovary cells. No crosslinking was detected in human MP fibroblasts. These data demonstrate that [125I]-[D-Bpa13,Tyr19]-MCH is a versatile photocrosslinking analogue of MCH suitable to identify MCH receptors in different cells and tissues; the MCH receptor in these cells appears to have the size of a G protein-coupled receptor, most likely with a varying degree of glycosylation.
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PMID:(D-(p-benzoylphenylalanine)13, tyrosine19)-melanin-concentrating hormone, a potent analogue for MCH receptor crosslinking. 1036 6

It is known that alpha-MSH augments cAMP levels in rat brain slices containing accumbens and caudate-putamen nuclei. In this study we examined: a) the effect of other neuropeptides: MCH and NEI, on this cyclic nucleotide; b) if the effects of alpha-MSH on cAMP production can be modulated by addition of MCH or NEI to the incubation medium. Both MCH and NEI (3.6 microM) increased the production of cAMP, whereas at doses of 0.6 microM exerted no effects. When alpha-MSH 0.6 microM was added with NEI or MCH (0.6 microM), only MCH blocked the increase in the cAMP induced by alpha-MSH. Neither MCH nor NEI at the highest dose used (3.6 microM) had any additive effect on AMPc when added together with alpha-MSH. We conclude that, at a high concentration, (MCH/NEI)-like peptides can use the intracellular signal transduction linked to cyclic nucleotides in the CNS.
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PMID:Effects and interactions between alpha-MSH and MCH/NEI upon striatal cAMP levels. 1046 13

Agouti protein and agouti-related protein (AGRP) antagonize alpha-melanocyte-stimulating hormone that binds to and activates the melanocortin-4 receptor (MC4-R) in the hypothalamus, thereby stimulating food intake. Melanin-concentrating hormone (MCH) and orexin are orexigenic peptides that specifically are synthesized in the lateral hypothalamus. MCH gene expression was augmented in A(y)/a (agouti) mice which overexpress agouti protein, but orexin mRNA was not. AGRP administered intracerebroventricularly into wild-type rats augmented MCH but not orexin gene expression. Also, SHU9119, a peptidergic antagonist of MC4-R, increased only MCH mRNA. These findings indicate that interruption of signaling at MC4-R activates the MCH but not the orexin gene. The biosyntheses of MCH and orexin are regulated through different pathways.
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PMID:Differential regulation of melanin-concentrating hormone and orexin genes in the agouti-related protein/melanocortin-4 receptor system. 1065 18

A novel RIA was used to examine the release of agouti-related protein-like immunoreactivity (AGRP-LI) from perfused rat hypothalamic tissue slices and to characterize AGRP-LI in rat serum. A continuous low level basal AGRP-LI release was observed from hypothalami of rats fed ad libitum before the rats were killed. Basal AGRP-LI release was 3-fold greater in rats fasted 48 h. In fasted animals leptin dose-dependently suppressed basal AGRP-LI release. In fed animals no change in basal AGRP-LI release was detected in response to 10(-6) M alpha-MSH, orexin B, melanin-concentrating hormone, or serotonin. HPLC analysis of AGRP-LI in rat serum identified a single peak that eluted in close proximity to synthetic AGRP (87-132) and mouse [Leu127Pro]AGRP and that was identical to the peak seen in hypothalamic and adrenal tissue extracts. The serum concentration of AGRP-LI in rats fed ad libitum was 0.865+/-0.323 nmol/liter (mean +/- SE). Food deprivation resulted in a slow, but statistically significant rise in serum immunoreactivity at 48 h [1.174+/-0.118 nmol/liter (mean +/- SE)]. Bilateral adrenalectomy did not change serum levels of AGRP-LI. These studies demonstrate that in the rat there are different levels of basal hypothalamic AGRP-LI release in fed and fasted states and that in the fasted rat this release can be profoundly suppressed by leptin. These studies also suggest that AGRP is present in the systemic circulation of rats.
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PMID:Agouti-related protein-like immunoreactivity: characterization of release from hypothalamic tissue and presence in serum. 1083 Feb 75

The mouse mahogany gene encodes a protein that is involved in the suppression of diet-induced obesity. We studied the ability of its widely conserved C-terminal fragment to cross the blood-brain barrier (BBB) in mice. Multiple-time regression analysis showed that the entry rate (K(i)) of (125)I-mahogany (1377-1428) from blood-to-brain was 5.5 x 10(-4) ml/g. min. After coinjection of unlabeled mahogany (1377-1428), the K(i) was significantly decreased, showing the self-inhibition characteristic of a saturable transport mechanism. The excess mahogany (1377-1428) did not change the influx rate of (99m)Tcalbumin, the vascular control, indicating a lack of disruption of the BBB. Statistically significant cross-inhibition was not seen with agouti-related protein (83-132), melanin-concentrating hormone, epidermal growth factor, leptin, a melanocortin-4 receptor antagonist, or alpha-melanocyte-stimulating hormone. HPLC showed that most of the injected (125)I-mahogany (1377-1428) reached the brain intact, and capillary depletion with washout showed that most of it reached the parenchyma. There was no brain-to-blood efflux system for mahogany (1377-1428) but rather retention after i.c.v. administration, and the octanol/buffer partition coefficient showed low lipophilicity. Thus, the results show that the C-terminal peptide product encoded by the mahogany gene crosses the BBB by a transport mechanism that is saturable. The ability of this system to be regulated indicates the therapeutic potential of mahogany (1377-1428) in the treatment of obesity.
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PMID:Mahogany (1377-1428) enters brain by a saturable transport system. 1090 Feb 42

The neuropeptides, monoamines and many drugs involved with modulating food intake and fat stores have reciprocal effects on sympathetic activity and thermogenesis. Both serotonin, acting through 5HT1B/2C receptors, and norepinephrine acting through beta2 and/or beta3 receptors reduce food intake and augment sympathetic activity. Neuropeptide Y, beta-endorphin, orexin, galanin and melanin concentrating hormone all increase food intake and, where tested, reduce sympathetic activity. In contrast, a larger number of peptides including cholecystokinin, corticotrophin-releasing hormone/urocortin, enterostatin, leptin, CART and alpha-MSH reduce food intake and increase sympathetic activity. Nicotine, prostaglandin, dexfenfluramine and sibutramine also have this reciprocal effect on feeding and sympathetic nervous system (SNS) activity. Chronic administration of neuropeptide Y (NPY) can produce chronically increased food intake and obesity. This syndrome is similar to the ventromedial hypothalamus (VMH) syndrome and suggests that NPY must be acting as an inhibitory signal to stimulate a feeding system and inhibit sympathetic activity. The melanocortin receptor system may be particularly important in modulating food intake, because a transgenic mouse which does not express melanocortin-4 receptors is massively overweight. Adrenal glucocorticoids are important in obesity since adrenalectomy will reverse or prevent the development of all forms of obesity. The clinical importance of the sympathetic nervous system and food intake is emphasized by the inverse relation of sympathetic activity and body fat. The inhibition of food intake, lower body fat stores and higher energy expenditure in smokers also support this hypothesis. The reciprocal relationship between food intake and sympathetic activity is robust, suggesting that beta receptors in the periphery and brain may be involved in the control of feeding and a reduction in food intake in humans accounts for most of the weight loss with ephedrine and caffeine. We conclude that the inhibition of feeding by activating the SNS is an important satiety system which helps regulate body fat stores.
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PMID:Reciprocal relation of food intake and sympathetic activity: experimental observations and clinical implications. 1099


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