UNIPROT:P01189 - FACTA Search

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Query: UNIPROT:P01189 (beta-endorphin)
21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin affects body weight by decreasing food intake, activating the sympathetic nervous system and regulating neuroendocrine function. This type of regulation is a hallmark of hypothalamic control, which typically integrates autonomic, endocrine and behavioral responses. We have performed a series of experiments investigating hypothalamic pathways underlying these actions of leptin. We found that leptin activates neurons that coexpress pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) mRNA. These neurons innervate several sites, including sympathetic preganglionic neurons in the spinal cord, neurons in the paraventricular hypothalamic nucleus (PVH), and melanin-concentrating hormone and orexin neurons in the lateral hypothalamic area (LHA). Following leptin administration, POMC neurons express both Fos and suppressor of cytokine signalling-3 (SOCS-3) mRNA. In contrast, leptin induced SOCS-3 expression in neuropeptide Y (NPY) neurons but not Fos, suggesting that leptin acts differentially on NPY and POMC cells. We also investigated potential downstream targets of leptin responsive NPY and POMC neurons by assessing the distribution of the melanocortin 4 receptor (MC4-R) mRNA and Y1 and Y5 NPY receptor mRNA in chemically defined neurons. We found dense MC4-R mRNA expression in several sites including the PVH and LHA. Using dual-label in situ hybridization we found that MC4-R mRNA is coexpressed in PVH cells expressing pro-TRH mRNA. We also found Y1 and Y5 NPY receptor mRNA in the PVH in patterns very similar to that of MC4R, suggesting that these receptors may be coexpressed on at least some PVH neurons. These results provide a neuroanatomic framework explaining the endocrine, autonomic and behavioral effects of leptin.
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PMID:Hypothalamic pathways underlying the endocrine, autonomic, and behavioral effects of leptin. 1184 Feb 21

To elucidate the molecular basis of the interaction of the native dodecapeptide gamma-MSH with the melanocortin receptors, we performed a structure-activity study in which we systematically replaced l-Ala in each position of this peptide. Here we report the binding affinity and agonist potency on human MC3R, MC4R and MC5R. Intracellular cAMP concentration was measured on CHO cells, and binding assays were carried out using membranes prepared from these cell lines which stably express hMC3R, hMC4R and hMC5R. Our results indicate that the last four amino acids in the C-terminal region of gamma-MSH are not important determinants of biological activity and selectivity at human melanocortin receptors. Interesting results were obtained when l-Ala was substituted for His6, Phe7, Arg8 and Trp9. For these peptides, the affinity and activity at all three human receptors (MC3R, MC4R and MC5R) decreased significantly, demonstrating that the His-Phe-Arg-Trp sequence in gamma-MSH is important for activity at these three melanocortin receptors. Similar results were obtained when Met3 was replaced with l-Ala, suggesting the importance of this position in the interaction with all three receptors. This study highlights the role played by the His-Phe-Arg-Trp sequence in receptor binding and in agonist activity of gamma-MSH.
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PMID:Synthesis and biological evaluation on hMC3, hMC4 and hMC5 receptors of gamma-MSH analogs substituted with L-alanine. 1196 77

A chronic minor imbalance between energy intake and energy expenditure may lead to obesity. Both lean and obese subjects eventually reach energy balance and their body weight regulation implies that the adipose tissue mass is "sensed", leading to appropriate responses of energy intake and energy expenditure. The cloning of the ob gene and the identification of its encoded protein, leptin, have provided a system signaling the amount of adipose energy stores to the brain. Leptin, a hormone secreted by fat cells, acts in rodents via hypothalamic receptors to inhibit feeding and increase thermogenesis. A feedback regulatory loop with three distinct steps has been identified: (1) a sensor (leptin production by adipose cells) monitors the size of the adipose tissue mass; (2) hypothalamic centers receive and integrate the intensity of the leptin signal through leptin receptors (LRb); (3) effector systems, including the sympathetic nervous system, control the two main determinants of energy balance-energy intake and energy expenditure. While this feedback regulatory loop is well established in rodents, there are many unsolved questions about its applicability to body weight regulation in humans. The rate of leptin production is related to adiposity, but a large portion of the interindividual variability in plasma leptin concentration is independent of body fatness. Gender is an important factor determining plasma leptin, with women having markedly higher leptin concentrations than men for any given degree of fat mass. The ob mRNA expression is also upregulated by glucocorticoids, whereas stimulation of the sympathetic nervous system results in its inhibition. Furthermore, leptin is not a satiety factor in humans because changes in food intake do not induce short-term increases in plasma leptin levels. After its binding to LRb in the hypothalamus, leptin stimulates a specific signaling cascade that results in the inhibition of several orexigenic neuropeptides, while stimulating several anorexigenic peptides. The orexigenic neuropeptides that are downregulated by leptin are NPY (neuropeptide Y), MCH (melanin-concentrating hormone), orexins, and AGRP (agouti-related peptide). The anorexigenic neuropeptides that are upregulated by leptin are alpha-MSH (alpha-melanocyte-stimulating hormone), which acts on MC4R (melanocortin-4 receptor); CART (cocaine and amphetamine-regulated transcript); and CRH (corticotropin-releasing-hormone). Obese humans have high plasma leptin concentrations related to the size of adipose tissue, but this elevated leptin signal does not induce the expected responses (i.e., a reduction in food intake and an increase in energy expenditure). This suggests that obese humans are resistant to the effects of endogenous leptin. This resistance is also shown by the lack of effect of exogenous leptin administration to induce weight loss in obese patients. The mechanisms that may account for leptin resistance in human obesity include a limitation of the blood-brain-barrier transport system for leptin and an inhibition of the leptin signaling pathways in leptin-responsive hypothalamic neurons. During periods of energy deficit, the fall in leptin plasma levels exceeds the rate at which fat stores are decreased. Reduction of the leptin signal induces several neuroendocrine responses that tend to limit weight loss, such as hunger, food-seeking behavior, and suppression of plasma thyroid hormone levels. Conversely, it is unlikely that leptin has evolved to prevent obesity when plenty of palatable foods are available because the elevated plasma leptin levels resulting from the increased adipose tissue mass do not prevent the development of obesity. In conclusion, in humans, the leptin signaling system appears to be mainly involved in maintenance of adequate energy stores for survival during periods of energy deficit. Its role in the etiology of human obesity is only demonstrated in the very rare situations of absence of the leptin signal (mutations of the leptin gene or of the leptin receptor gene), which produces an internal perception of starvation and results in a chronic stimulation of excessive food intake.
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PMID:Leptin signaling, adiposity, and energy balance. 1207 65

Identifying the role of the melanocortin system in regulating energy homeostasis has relied on both genetic and pharmacological studies. The key findings included 1) that the coat color phenotype in the lethal yellow (A(Y)/a) mouse is due to antagonism of the melanocortin-1 receptor (MC1R) by the agouti gene product; 2) the MC3R and MC4R are expressed in CNS centers involved in energy homeostasis, and 3) the combined results of pharmacological studies showing that agouti is an antagonist of the MC4R and transgenic studies showing that inhibition or loss of the MC4R recapitulate the lethal yellow phenotype. Pro-opiomelanocortin (POMC), MC3R, and MC4R knockouts are obese and are now being used to further analyze melanocortin receptor function. The obesity phenotype observed in the MC3R and MC4R knockouts (KO) differ markedly. MC4RKO mice are hyperphagic, do not regulate pathways that increase energy expenditure (diet-induced thermogenesis) and physical activity in response to hyperphagia, and can develop type 2 diabetes. In contrast, MC3R deficient mice are not hyperphagic, have a normal metabolic response to increased energy consumption, and do not develop diabetes. The mechanism underlying the increased adiposity in the MC3R knockout remains unclear, but might be related to changes in nutrient partitioning or physical activity.
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PMID:The melanocortin receptors: lessons from knockout models. 1235 99

Melanocortins are derived from posttranslational processing of the precursor protein pro-opiomelanocortin (POMC). The central melanocortinergic system consists of endogenous agonist alpha-melanocyte-stimulating hormone, the naturally occurring antagonist Agouti-related protein (AGRP), and two melanocortin receptors (MC3R, MC4R). Activation of central melanocortin receptors inhibits feeding and leads to weight loss, whereas blockade of the central melanocortin signaling pathway increases food consumption and promotes weight gain. This review will focus on the role of central melanocortin signaling in eating behavior and will evaluate studies of the neural pathways of POMC and AGRP systems, the effects of the central melanocortinergic system on food intake and body weight, and the regulation of hypothalamic POMC and AGRP neurons in response to altered feeding state and energy balance. In addition, this review will explore what is known about the interplay between the central melanocortinergic system and peripheral signals of energy homeostasis, i.e., leptin and glucocorticoids. Furthermore, evidence will be presented that genetic defects within the melanocortin signaling system are involved in determining susceptibility to obesity and anorexia in humans, and the therapeutic potential of melanocortin agonists and antagonists in the treatment of these disorders will be discussed.
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PMID:Role of central melanocortin signaling in eating disorders. 1239 56

The melanocortin pathway is involved in the regulation of several physiological functions including skin pigmentation, steroidogenesis, obesity, energy homeostasis, and exocrine gland function. This melanocortin pathway consists of five known G-protein coupled receptors, endogenous agonists derived from the proopiomelanocortin (POMC) gene transcript, the endogenous antagonists Agouti and the Agouti-related protein (AGRP) and signals through the intracellular cAMP signal transduction pathway. The endogenous melanocortin agonists contain the putative message sequence "His-Phe-Arg-Trp," postulated to be important for melanocortin receptor molecular recognition and stimulation. Herein, we report a tetrapeptide library, based upon the template Ac-His-D-Phe-Arg-Trp-NH(2), consisting of 20 members that have been modified at the Trp(9) position (alpha-MSH numbering) and pharmacologically characterized for agonist activity at the mouse melanocortin receptors MC1R, MC3R, MC4R, and MC5R. Results from this study yielded compounds that ranged in pharmacological properties from equipotent to a loss of melanocortin receptor activity at up to 100 microM concentrations. Interestingly, modification of the Trp(9) in the tetrapeptide template at the MC1R resulted in only up to a 220-fold potency change, while at the MC4R and MC5R, up to a 9700-fold decrease in potency was observed, suggesting the MC1R is more tolerant of the modifications examined herein. The most notable results of this study include identification that the Trp(9) indole moiety in the tetrapeptide template is important for melanocortin-3 receptor agonist potency, and that this position can be used to design melanocortin ligands possessing receptor selectivity for the peripherally expressed MC1 and MC5 versus the centrally expressed MC3 and MC4 receptors. Specifically, the Ac-His-D-Phe-Arg-Tic-NH(2) and the Ac-His-D-Phe-Arg-Bip-NH(2) tetrapeptides possessed nanomolar MC1R and MC5R potency but micromolar MC3R and MC4R agonist potency. Additionally, these studies identified that substitution of the Trp amino acid with either Nal(2') or D-Nal(2') resulted in equipotent melanocortin receptor potency, suggesting that the chemically reactive Trp indole side chain may be replaced with the nonreactive Nal(2') moiety for the design of nonpeptide melanocortin receptor agonists.
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PMID:Structure-activity relationships of the melanocortin tetrapeptide Ac-His-D-Phe-Arg-Trp-NH2 at the mouse melanocortin receptors. 4. Modifications at the Trp position. 1247 57

Heterozygous mutations in the coding region of the serpentine Melanocortin 4 receptor are the most common genetic cause of human obesity described to date. There are still conflicting data regarding the overall prevalence of such mutations in obesity and limited information is available on the functional defects caused by most obesity-associated MC4R mutations. We report here the screening for mutations in the coding region of the MC4R of a new cohort of 172 patients presenting with severe childhood obesity and a family history of obesity. Three heterozygous MC4R mutations (Ser127Leu, Ala244Glu and Pro299His) were found in three patients of this cohort (1.74%), confirming that such mutations are implicated in a significant number of childhood obesity cases. A functional analysis of these mutant receptors, in addition to 11 other childhood obesity-associated MC4R mutations, indicates that they all alter the activation of the receptor by the endogenous agonist alpha-MSH. To further examine the functional defects caused by childhood obesity-associated MC4R mutations, we developed a novel, sensitive technique to quantitatively analyze the effect of a mutation on MC4R cell surface expression. Using this method we analyzed the cell surface expression of all the 14 described childhood obesity-associated MC4R missense mutations. We demonstrate that 81.3% of childhood obesity-associated heterozygous MC4R mutations lead to intracellular retention of the receptor. This result has implications for the potential pharmacologic rescue of childhood obesity-associated MC4R mutations and for the treatment of patients presenting with this condition.
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PMID:Intracellular retention is a common characteristic of childhood obesity-associated MC4R mutations. 1249 95

The melanotropin peptides alpha-MSH, gamma-MSH, and beta-MSH are believed to be the natural ligands for the four melanocortin receptors, MC1R, MC3R, MC4R, and MC5R. However, these peptides generally have low selectivity for these receptors. We report on some approaches to the development of selective agonists and antagonists peptide ligands for these receptors.
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PMID:Exploring the stereostructural requirements of peptide ligands for the melanocortin receptors. 1285 Dec 93

PT-141, a synthetic peptide analogue of alpha-MSH, is an agonist at melanocortin receptors including the MC3R and MC4R, which are expressed primarily in the central nervous system. Administration of PT-141 to rats and nonhuman primates results in penile erections. Systemic administration of PT-141 to rats activates neurons in the hypothalamus as shown by an increase in c-Fos immunoreactivity. Neurons in the same region of the central nervous system take up pseudorabies virus injected into the corpus cavernosum of the rat penis. Administration of PT-141 to normal men and to patients with erectile dysfunction resulted in a rapid dose-dependent increase in erectile activity. The results suggest that PT-141 holds promise as a new treatment for sexual dysfunction.
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PMID:PT-141: a melanocortin agonist for the treatment of sexual dysfunction. 1285 3

The melanocortin (MC) gamma3-MSH is believed to signal through the MC3 receptor. We showed that it induces a sustained increase in intracellular free calcium levels ([Ca(2+)](i)) in a subpopulation of pituitary cells. Most of the cells responding to gamma3-MSH express more than one pituitary hormone mRNA. The effect of gamma3-MSH is blocked by SHU9119, a MC3R and MC4R antagonist, in only 50% of the responsive cells, suggesting that in half of these cells the mediating receptor is not the MC3R. Low picomolar doses of gamma3-MSH increase [Ca(2+)](i) in the growth hormone (GH)- and prolactin (PRL)-secreting GH3 cell line. gamma2-MSH and alpha-MSH display a similar effect. SHU9119 does not affect the gamma3-MSH-induced [Ca(2+)](i) response. MTII, a potent synthetic agonist of the MC3R, MC4R, and MC5R, also shows no or low potency in increasing [Ca(2+)](i). By means of RT-PCR, the mRNA of the MC2R, MC3R, and MC4R receptors is undetectable. Experiments testing gamma2-MSH analogues with single alanine replacements show that, unlike the classic MCRs, the His(5)-Phe(6)-Arg(7)-Trp(8) sequence in gamma2-MSH is not a core sequence for activating the gamma-MSH receptor in GH3 cells, whereas Met(3) is essential. Low nanomolar doses of gamma-MSH increase intracellular cAMP levels. Blockade of protein kinase A abolishes the [Ca(2+)](i) responses to gamma3-MSH. gamma2-MSH increases binding of [S(35)]GTPgammaS to membrane preparations of GH3 cells. The pharmacological characteristics of gamma-MSH peptides and analogues on [Ca(2+)](i) and the signal-transduction pathways present strong evidence for the expression of a hitherto uncharacterized gamma-MSH receptor in GH3 cells, belonging to the G protein-coupled receptor family.
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PMID:Gamma-MSH peptides in the pituitary: effects, target cells, and receptors. 1285 7

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