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)

This review focuses on the expression, content, and release of neuropeptides and on their role in the development of obesity in animal models with single-gene mutations. The balance between neuropeptides that contribute to the control of feeding behavior is profoundly and variously altered in these models, supporting the concept of the existence of several types of obesity. The hypothalamic neuropeptide Y (NPY) and the pro-opiomelanocortin (POMC) systems are the networks most studied in relation to energy intake. Both receive information about the nutritional status and the level of energy storage through insulin and leptin signaling mediated by specific receptors located on POMC and NPY neurons present predominantly in the arcuate nucleus (ARC). When leptin signaling is defective, through a defect in either the receptor (Zucker fa/fa rat, cp/cp rat, and db/db mouse) or in the peptide itself (ob/ob mouse), the NPY system is upregulated as shown by mRNA overexpression and increased peptide release, whereas the content and/or release of some inhibitory peptides (neurotensin, cholecystokinin) are diminished. For the POMC system, there is a complex interaction between the tonic inhibition of food intake exerted by alpha-melanocyte-stimulating hormone (alpha-MSH) and the Agouti-related protein at the level of the type 4 melanocortin receptor. The latter peptide is coexpressed with NPY in the ARC. Corticotropin-releasing factor (CRF) is the link between food intake and environmental factors. It not only inhibits food intake and prevents weight gain, likely through hypothalamic effects, but also activates the hypothalamo-pituitary axis and therefore contributes to energy storage in adipose tissue. The factors that prod the CRF system toward the hypothalamic or hypothalamo-pituitary axis system remain to be more clearly defined (comodulators, connections between limbic system and ARC, cellular location, and type of receptors, etc. ). The pathways used by all of these neuromodulators include numerous brain areas, but some interest has returned to the classic ones such as the ventromedial and lateral hypothalamic areas because of the recent discovery of some peptides (orexins and melanin-concentrating hormone for the lateral hypothalamus) and receptors (CRF type 2 in the ventromedial hypothalamus). All of these pathways are redundant and function in a coordinated manner and sometimes by the novel expression of a peptide in an unusual area. The importance of such a phenomenon in obesity remains to be determined. Even if single-gene mutations are exceptions in human obesity, the study of genetic animal models of obesity has greatly contributed to the understanding of the regulation of feeding behavior and will allow researchers to develop new drug treatments for obesity that have to be associated with drastic changes in lifestyle (feeding, work habits, and physical activity) for a complete efficiency.
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PMID:Neuropeptides and obesity. 1105 97

Gonadal steroids influence food intake and body weight. Although the specific mechanisms underlying these effects are not clear, a consideration of their effects in the context of current models of energy homeostasis may ultimately lead to the identification of these mechanisms. When compared with leptin, the prototypical humoral signal of energy balance, sex steroids share many common properties related to food intake and body weight. Specifically, gonadal steroids circulate in proportion to fat mass and current energy balance, and administration of these compounds influences food intake, energy expenditure, body weight, and body composition. Moreover, both estrogens and androgens modulate central nervous system effectors of energy homeostasis that are targets for the action of leptin, including pathways that contain neuropeptide Y, pro-opiomelanocortin, or melanin-concentrating hormone. Sex steroids and leptin also regulate one another's production. Although gonadal steroids, unlike leptin, are clearly not critical to the maintenance of normal energy homeostasis, they do appear to function as physiologic modulators of this process. Identifying the specific central mediators of their effects will contribute to our understanding of their role in energy homeostasis.
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PMID:Gonadal steroids and energy homeostasis in the leptin era. 1105 99

This study provides an analysis of the chemoarchitecture of the posterior hypothalamic area (PHA) and a retrograde transport analysis of inputs to the PHA in the rat. The chemoarchitectural analysis reveals that the majority of PHA neurons contain glutamate. Hypocretin, melanin concentrating hormone, tyrosine hydroxylase, neuropeptide Y and gamma-aminobutyric acid are also found in subsets of PHA neurons, and fibers immunoreactive for these substances as well as for serotonin, dopamine-beta-hydroxylase and met-enkephalin are observed in the area and aid in the delineation of its borders. The retrograde tracing study demonstrates that the PHA receives input from multiple, diverse neuron populations. Descending projections to the PHA arise from the limbic forebrain (cingulate cortex and lateral septum) and both the medial and lateral hypothalamus. Subcortical visual nuclei, including the ventral lateral geniculate nucleus and intergeniculate leaflet, pretectal area, and superior colliculus, and the subthalamus (zona incerta, fields of Forel) also project to the PHA. Ascending projections to the PHA arise from brainstem cholinergic nuclei, the reticular formation, midbrain raphe nuclei, periaqueductal gray and parabrachial nucleus. Retrograde transport studies using the psuedorabies virus (PRV) demonstrate that the PHA receives input indirectly from the hippocampus, amygdala and suprachiasmatic nucleus through circuits including nuclei in the limbic forebrain and hypothalamus. These data suggest that the PHA is important in the neural control of behavioral state, modulating aspects of hippocampal, autonomic and cortical function as they relate to the elaboration of adaptive behavior.
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PMID:The posterior hypothalamic area: chemoarchitecture and afferent connections. 1116 82

The effects of single injections of 2-deoxyglucose or 2-mercaptoacetate on the expression of mRNA of neuropeptide Y, pro-opiomelanocortin, and melanin-concentrating hormone in rat hypothalamus were studied by in situ hybridization in order to elucidate the role of these neuropeptides in the mechanisms of alimentary behavior caused by decreased levels of available fatty acids and glucose. The levels of neuropeptide Y mRNA in arcuate nuclei neurons are significantly increased under conditions of glucose deficiency, while the synthesis of melanin-concentrating hormone in the lateral hypothalamic neurons is increased in fatty acid deficiency. These data indicate that glyco- and lipodeprivation are different metabolic signals activating various neuropeptide systems responsible for alimentary behavior.
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PMID:Effects of blockers of carbohydrate and lipid metabolism on expression of mRNA of some hypothalamic neuropeptides. 1117 38

Feeding behavior results from complex interactions arising between numerous neuromediators, including classical neurotransmitters and neuropeptides present in hypothalamic networks. One way to unravel these complex mechanisms is to examine animal models with a deletion of genes coding for the different neuropeptides involved in the regulation of feeding. The aim of this review is to focus on feeding and body weight regulation in mice lacking neuropeptide Y (NPY), melanocortins (POMC), corticotropin-releasing hormone, melanin-concentrating hormone, or bombesin-like peptides respectively. The phenotypes, which relate to the deletion of gene coding for the peptides, rarely include changes in body weight and food intake, indicating therefore the existence of redundant mechanisms to compensate for the loss of the peptide. The phenotype is much more marked when the gene deletion is targeted towards the functioning of the peptidergic machinery, e.g. the receptors and especially the POMC and NPY receptors, as well as one subtype of bombesin receptor (BRS-3). These knockout models are also interesting when examining the role of environmental and social factors in the determination of feeding behavior. They have granted us better knowledge of all these integrated and complex mechanisms. Moreover, they are also valuable tools for pharmacological studies when specific antagonists are lacking. From the information obtained by the study of knockouts, it is possible to determine certain targets for selective drugs that could be efficient for the pharmacological treatment of obesity. However, at the present state of our knowledge, it seems necessary to target several peptides in order to get good results with weight loss. It will also be imperative to associate these multitherapies with changes in eating and behavioral habits, in order to obtain complete effectiveness and long-lasting results.
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PMID:KO's and organisation of peptidergic feeding behavior mechanisms. 1132 79

Previous studies on trout suggest that melanin-concentrating hormone (MCH) acts at both hypothalamic and pituitary levels to restrain the release of adrenocorticotropic hormone and hence cortisol during stress. Using in situ hybridization, the present work examined whether high rates of MCH secretion were associated with changes in the synthesis of arginine vasotocin (AVT), one of the corticotropin secretogogues. It also examined whether high endogenous MCH secretion restrains cortisol secretion during intense as well as mild stress, and how exogenous MCH affects the rise in plasma cortisol following injection stress. Trout were reared in black- or white-coloured tanks for 1 year or more to achieve maximal differences in MCH secretion. Following a mild stress, cortisol secretion was greater in black-reared fish with low MCH secretion which is in line with previous findings but, following a more severe stress, plasma cortisol concentrations were similar in the two groups. Injection of MCH into black-adapted fish restrained the stress-induced rise in plasma cortisol concentration during the first hour but did not affect final cortisol values. In two separate experiments, AVT mRNA levels were significantly lower in the hypothalamus of black-reared fish. Possible explanations for this include a greater negative-feedback restraint by cortisol, which is likely to rise higher in black-adapted fish during the moderate, daily stresses of aquarium life; or the possibility that exposure to a white background may be psychologically stressful, stimulating AVT transcription. The possibility that MCH directly stimulates AVT transcription cannot be excluded but seems less likely. The results suggest that while MCH may restrain the release of hypothalamo-pituitary stress hormones under moderately stressful conditions, it does not restrain AVT synthesis.
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PMID:Differences in arginine vasotocin gene transcripts and cortisol secretion in trout with high or low endogenous melanin-concentrating hormone secretion. 1132 49

We previously reported that the human melanoma cell line, SEKI, induces severe weight loss in nude mice. In the present study, we examined the expression of weight-regulating neuropeptide mRNAs in the hypothalamus of this cancer cachectic model by using a sensitive quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method and in situ hybridization. mRNA levels of neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH) in the whole hypothalamus were elevated significantly in the SEKI mice as compared with control mice. In situ hybridization showed that NPY and CRH mRNA were upregulated in the arcuate nucleus and the paraventricular nucleus, respectively. There were no significant differences in melanin-concentrating hormone (MCH), orexin (OX), and cholecystokinin mRNA levels between the SEKI and control mice. These results suggest that the NPYergic system is functioning in the rodent model of cancer cachexia; however, the role of the CRHergic system in energy homeostasis remains to be elucidated. This is the first report of the hypothalamic neuropeptide response to cachexia-inducing human cells.
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PMID:Hypothalamic appetite-regulating neuropeptide mRNA levels in cachectic nude mice bearing human tumor cells. 1158 96

Antagonist and agonist activities of chemically synthetized mouse agouti protein fragment (91-131) (AP91-131) at the melanocortin type-1 receptor (MC1-R) were assessed using B 16-F1 mouse melanoma cells in vitro and the following assay systems: (i) receptor binding, (ii) adenylate cyclase, (iii) tyrosinase, (iv) melanin production, and (v) cell proliferation. In competition binding studies AP91-131 was about 3-fold less potent than the natural agonist alpha-melanocyte-stimulating hormone (alpha-MSH) in displacing the radioligand [125I]-[Nle4, D-Phe7]-alpha-MSH (Ki 6.5 +/- 0.8 nmol/l). Alpha-MSH-induced tyrosinase activation and melanin production were completely inhibited by a 100-fold higher concentration of AP9 l -131; the IC50 values for AP91-131 in thetwo assay systems were 91 +/- 22 nM and 95 +/- 15 nM respectively. Basal melanin production and adenylate cyclase activity in the absence of agonist were decreased by AP91-131 with IC50 values of 9.6+/-1.8 nM and 5.0+/-2.4 nM, respectively. This indicates inverse agonist activity of AP91-131 similar to that of native AP. The presence of 10 nM melanin-concentrating hormone (MCH) slightly potentiated the inhibitory activity of AP91-131 in the adenylate cyclase and melanin assays. On the other hand, AP91-131 inhibited cell growth similar to alpha-MSH (IC50 11.0 +/- 2.1 nM; maximal inhibition 1.8-fold higher than that of alpha-MSH). Furthermore, MC1-R was down-regulated by AP91-131 with about the same potency and time-course as with alpha-MSH. These results demonstrate that AP91-131 displays both agonist and antagonist activities at the MC1-R and hence that it is the cysteine-rich region of agouti protein which inhibits and mimics the different alpha-MSH functions, most likely by simultaneous modulation of different intracellular signalling pathways.
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PMID:Antagonist and agonist activities of the mouse agouti protein fragment (91-131) at the melanocortin-1 receptor. 1169 71

Melanin-concentrating hormone (MCH) and alpha-melanocyte-stimulating hormone (alpha-MSH) are known to exhibit mostly functionally antagonistic, but in some cases agonistic activities, e.g., in pigment cells and in the brain. Neuropeptide E-I (NEI) displays functional MCH-antagonist and MSH-agonist activity in different behavioral paradigms; the role of neuropeptide G-E (NGE) is not known. This study addressed the question of possible molecular interactions between alpha-MSH, MCH and the MCH-precursor-derived peptides NEI and NGE at the level of the pigment cell MCH receptor subtype (MCH-Rpc) and the different melanocortin (MC) receptors. Radioreceptor assays using [125I]MCH, [125l]alpha-MSH and [125I]NEI as radioligands and bioassays were performed with MCI-R-positive and MC1-R-negative mouse B16 melanoma cells and with COS cells expressing the different MC receptors. The IC50s of alpha-MSH and NEI or NGE for [125I]MCH displacement from mouse MCH-Rpc were 80-fold and, respectively, >300-fold higher than that of MCH, and the IC50s for MCH and NEI or NGE for [125I]alpha-MSH displacement from mouse MC1-R were 50,000-fold and >200,000-fold higher than that of alpha-MSH. No high-affinity binding sites for NEI were detected on B16 melanoma cells and there was no significant displacement of [1251]alpha-MSH by MCH, NEI or NGE with MC3-R, MC4-R and MC5-R expressed in COS cells. At concentrations of 100 nM to 10 microM, however, MCH, NEI and NGE induced cAMP formation and melanin synthesis which could be blocked by agouti protein or inhibitors of adenylate cyclase or protein kinase A. This shows that mammalian MCH-precursor-derived peptides may mimic MSH signalling via MC1-R activation at relatively high, but physiologically still relevant concentrations, as e.g. found in autocrine/paracrine signalling mechanisms.
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PMID:Interaction of melanin-concentrating hormone (MCH), neuropeptide E-I (NEI), neuropeptide G-E (NGE), and alpha-MSH with melanocortin and MCH receptors on mouse B16 melanoma cells. 1169 76

Leptin, a hormone secreted from the adipose tissue, is involved in the regulation of food intake and neuroendocrine function, by modulation of the expression and/or function of various neuropeptides in the hypothalamus. The long isoform (OB-Rb) is the major signaling form of the leptin receptor in the hypothalamus. We have used double-labeling immunohistochemistry to examine the extent of OB-Rb expression in neurochemically defined cell types in the ovine hypothalamus. OB-Rb-like immunoreactivity was widespread within cells localized to the periventricular, paraventricular, supraoptic, dorsomedial hypothalamic, ventromedial hypothalamic and arcuate nuclei, as well as the median eminence, perifornical, anterior hypothalamic and lateral hypothalamic areas and the zona incerta. Double-labeling showed expression of OB-Rb in 59.6+/-6.0% neuropeptide Y-containing cells, 60.8+/-4.7% galanin-containing cells, 89.8+/-2.65% pro-opiomelanocortin-containing cells, 73.4+/-3.5% tyrosine hydroxylase-containing cells and 31.8+/-2.8% corticotropin-releasing factor-containing cells. Interestingly 100% of melanin-concentrating hormone and orexin positive cells were also OB-Rb immunoreactive. These data provide semi-quantitative information on the extent to which various cell types express OB-Rb in the hypothalamus. Expression of OB-Rb within specific neuropeptidergic neurons provides evidence for the direct action of leptin upon the various neurochemical systems that regulate food intake, neuroendocrine and autonomic function in the brain.
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PMID:Immunohistochemical characterization of localization of long-form leptin receptor (OB-Rb) in neurochemically defined cells in the ovine hypothalamus. 1171 11


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