Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A dysregulation in the hypothalamic neuropeptide systems involved in the control of appetite has previously been shown in models of diet-induced obesity. In the present study, male Sprague-Dawley rats were rendered obese by a highly palatable cafeteria-style diet over 20 weeks, while control rats had access to standard laboratory chow. Feeding responses to alpha-melanocyte stimulating hormone (alpha-MSH), an anorectic peptide and neuropeptide Y (NPY), a potent orexigenic agent were investigated in diet-induced obese and control animals. In addition, endogenous hypothalamic peptide levels were determined in these animals. Intracerebroventricular injections of either 4 nmol alpha-MSH or saline vehicle were given 10 min prior to the onset of the dark phase. Diet-induced obese rats had significantly enhanced nocturnal inhibitory feeding responses to alpha-MSH (P<0.05). The orexigenic feeding response induced by 1 nmol NPY was similar for both groups. At sacrifice, both alpha-MSH and NPY peptide content were selectively reduced in the paraventricular nucleus (PVN) of these animals (P<0.05). Although diet-induced obesity had no effect on responses to NPY, the significantly greater inhibition of nocturnal feeding by alpha-MSH and reduction in PVN alpha-MSH peptide level, suggests melanocortinergic signalling may be reduced in obesity which may account for the hyperphagia of these animals when presented with a palatable diet.
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PMID:Enhanced inhibitory feeding response to alpha-melanocyte stimulating hormone in the diet-induced obese rat. 1117 58

The central melanocortin receptors, melanocortin-4 (MC4R) and melanocortin-3 (MC3R), are involved in the regulation of satiety and energy homeostasis. The MC4R in particular has become a pharmaceutical industry drug target due to its direct involvement in the regulation of food intake and its potential therapeutic application for the treatment of obesity-related diseases. The melanocortin receptors are stimulated by the native ligand, alpha-melanocyte stimulating hormone (alpha-MSH). The potent and enzymatically stable analogue NDP-MSH (Ac-Ser-Tyr-Ser-Nle-Glu-His-DPhe-Arg-Trp-Gly-Lys-Pro-Val-NH(2)) is a lead peptide for the identification of melanocortin amino acids important for receptor molecular recognition and stimulation. We have synthesized nine peptide fragments of NDP-MSH, deleting N- and C-terminal amino acids to determine the "minimally active" sequence of NDP-MSH. Additionally, five peptides were synthesized to study stereochemical inversion at the Phe 7 and Trp 9 positions in attempts to increase tetra- and tripeptide potencies. These peptide analogues were pharmacologically characterized at the mouse melanocortin MC1, MC3, MC4, and MC5 receptors. This study has identified the Ac-His-DPhe-Arg-Trp-NH(2) tetrapeptide as possessing 10 nM agonist activity at the brain MC4R. The tripeptide Ac-DPhe-Arg-Trp-NH(2) possessed micromolar agonist activities at the MC1R, MC4R, and MC5R but only slight stimulatory activity was observed at the MC3R (at up to 100 microM concentration). This study has also examined to importance of both N- and C-terminal NDP-MSH amino acids at the different melanocortin receptors, providing information for drug design and identification of putative ligand-receptor interactions.
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PMID:Characterization of melanocortin NDP-MSH agonist peptide fragments at the mouse central and peripheral melanocortin receptors. 1140 61

Mutations in the melanocortin-4 receptor (MC4-R) cause obesity in both mice and humans, and the receptor is presumed to have an important role in the regulation of energy homeostasis. The MC4-R is expressed in discrete sets of neurons in the central nervous system, and thus it has been technically difficult to study the regulation of expression and the signaling mechanisms of this receptor. We report here a neuronal cell line that exhibits endogenous functional expression for the MC4-R. Initially, RT-PCR analysis showed the presence of MC4-R RNA in the hypothalamic GT1-1 and GT1-7 cells. In addition, GT1-7 cells expressed melanocortin-3 receptor while the GT1-1 subclone specifically expressed predominantly the MC4-R RNA. High-affinity binding sites were demonstrated in the GT1-1 and GT1-7 cells for NDP-alpha melanocyte-stimulating hormone (MSH; K(i) = 1.1 x 10(-10) and 1.8 x 10(-10) M) and agouti-related protein (AGRP; K(i) = 1.548 x 10(-9) and 1.663(-9) M). alpha-MSH-stimulated cAMP production in GT1-1 cells with an EC(50) of 2.2 x 10(-8) M, and cAMP production was inhibited in the presence of AGRP, an endogenous antagonist of the MC4-R. Stimulation of gonadotropin-releasing hormone (GnRH) secretion was achieved with 1 nM to 1 microM concentrations of NDP-alpha-MSH while no GnRH secretion was observed when the GT1-1 cells were treated with AGRP. The data presented here show that GT1-1 cells specifically express a functional MC4-R that couples to GnRH release.
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PMID:Expression of functional melanocortin-4 receptor in the hypothalamic GT1-1 cell line. 1152 21

The agouti protein regulates pigmentation in the mouse hair follicle producing a black hair with a subapical yellow band. Its effect on pigmentation is achieved by antagonizing the binding of alpha-melanocyte stimulating hormone (alpha-MSH) to melanocortin 1 receptor (Mc1r), switching melanin synthesis from eumelanin (black/brown) to phaeomelanin (red/yellow). Dominant mutations in the non-coding region of mouse agouti cause yellow coat colour and ectopic expression also results in obesity, type 11 diabetes, increased somatic growth and tumourigenesis. At least some of these pleiotropic effects can be explained by antagonism of other members of the melanocortin receptor family by agouti protein. The yellow coat colour is the result of agouti chronically antagonizing the binding of alpha-MSH to Mc1r and the obese phenotype results from agouti protein antagonizing the binding of alpha-MSH to Mc3r and/or Mc4r. Despite the existence of a highly homologous agouti protein in humans, agouti signal protein (ASIP), its role has yet to be defined. However it is known that human ASIP is expressed at highest levels in adipose tissue where it may antagonize one of the melanocortin receptors. The conserved nature of the agouti protein combined with the diverse phenotypic effects of agouti mutations in mouse and the different expression patterns of human and mouse agouti, suggest ASIP may play a role in human energy homeostasis and possibly human pigmentation.
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PMID:Agouti: from mouse to man, from skin to fat. 1183 51

The functional loss of both alleles of the human pro-opiomelanocortin (POMC) gene leads to a very rare syndrome of hypoadrenalism, red hair and early-onset obesity. In order to examine whether more subtle genetic variants in POMC might contribute to early-onset obesity, the coding region of the gene was sequenced in 262 Caucasian subjects with a history of severe obesity from childhood. Two children were found to be heterozygous for a missense mutation, R236G, which disrupts the dibasic cleavage site between beta melanocyte-stimulating hormone (beta-MSH) and beta-endorphin. Beta-TC3 cells transfected with the mutant POMC cDNA produced a mutant beta-MSH/beta-endorphin fusion protein. This fusion protein bound to the human melanocortin-4 receptor (hMC4R) with an affinity similar to its natural ligands, but had a markedly reduced ability to activate the receptor. This variant co-segregated with early-onset obesity over three generations in one family and was absent in 412 normal weight UK Caucasian controls. Combining the results in UK Caucasians with a new case-control study in French subjects and three previously published reports, mutations disrupting this processing site were present in 0.88% of subjects with early-onset obesity and 0.22% of normal-weight controls. These results suggest that the R236G mutation may confer an inherited susceptibility to obesity through the production of an aberrant fusion protein that has the capacity to interfere with central melanocortin signalling.
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PMID:A missense mutation disrupting a dibasic prohormone processing site in pro-opiomelanocortin (POMC) increases susceptibility to early-onset obesity through a novel molecular mechanism. 1216 61

The melanocortin system is implicated in multiple physiological pathways including pigmentation, inflammation, erectile function, feeding behavior, energy homeostasis, weight homeostasis, and exocrine gland function, just to list a few. The endogenous agonists for the melanocortin receptors include the gene transcripts derived from the proopiomelanocortin gene and include the core tetrapeptide His-Phe-Arg-Trp sequence postulated to be important for melanocortin receptor selectivity and stimulation. Posttranslational processing of the proopiomelanocortin derived agonists results in the N-terminal acetylation and C-terminal amidation of alpha-melanocyte stimulation hormone (alpha-MSH). In this study we generated 25 N-terminally "capped" tetrapeptides containing the core sequence X-His-D-Phe-Arg-Trp-NH(2) and pharmacologically characterized them at the mouse melanocortin MC(1) receptor, melanocortin MC(3) receptor, melanocortin MC(4) receptor, and melanocortin MC(5) receptor. The N-terminal "capping" groups consisted of linear, cyclic, or aromatic moieties and all resulted in full agonist activity at the melanocortin receptors examined in this study. Increasing aliphatic chain length increased potency of the tetrapeptide derivatives, with the addition of octanoyl capping group resulting in 70- to 110-fold increased tetrapeptide potency at the melanocortin MC(1) receptor (EC(50)=0.4 nM), melanocortin MC(3) receptor (EC(50)=4.0 nM), and melanocortin MC(4) receptor (EC(50)=0.4 nM) while only enhancing potency at the melanocortin MC(5) receptor (EC(50)=0.8 nM) by 8-fold, compared to the tetrapeptide His-D-Phe-Arg-Trp-NH(2). This octanoyl derivative surprisingly resulted in a 14-fold greater potency than alpha-MSH (EC(50)=5.4 nM) at the mouse melanocortin MC(4) receptor implicated in feeding behavior and obesity. The 3,3,3-triphenylpropionyl derivative resulted in greater than 14 microM agonist potencies at the melanocortin MC(1) receptor, melanocortin MC(3) receptor, and melanocortin MC(4) receptor and possessed a 140 nM agonist EC(50) value at the melanocortin MC(5) receptor. This 3,3,3-triphenylpropionyl-His-D-Phe-Arg-Trp-NH(2) peptide is a 100-fold selective agonist for the melanocortin MC(5) receptor, versus the other melanocortin receptors studied herein, and is the first melanocortin MC(5) receptor selective tetrapeptide derivative reported to date with nanomolar potency.
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PMID:Characterization of aliphatic, cyclic, and aromatic N-terminally "capped" His-D-Phe-Arg-Trp-NH2 tetrapeptides at the melanocortin receptors. 1259 Oct 94

To date five melanocortin receptors (MC-R) have been cloned, identified and shown to have a wide distribution throughout the body and likely many diverse functions. MC1-R, found on melanocytes, is involved in pigmentation, while MC2-R is the classic adrenocorticotropic (ACTH) receptor found on the adrenal cortex and adipocytes. MC3-R, MC4-R and MC5-R are in their infancy with regard to their characterization. MC4-R has generated wide interest for its involvement in obesity, whereas our own studies have indicated a role for MC3-R in experimental inflammation. An ACTH fragment unable to alter circulating corticosterone, ACTH-4-10, acts at murine MC3-R present on peritoneal macrophage to inhibit cytokine formation and subsequent neutrophil extravasation. These findings were confirmed using agonists with a higher degree of selectivity toward MC3-R, such as gamma-2-MSH and the synthetic mixed MC3/4-R agonist MTII. In vitro, all these agents were able to affect macrophage functions, including phagocytosis and production of the CXC chemokine KC. Besides using RT-PCR and cAMP formation assays, the involvement of MC3-R in the antiinflammatory actions of these melanocortins was validated with the antagonist SHU-9119. Together these experimental data support the notion that agonism at MC3-R can be used for the design of novel therapeutics for inflammatory conditions.
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PMID:MC3-R as a novel target for antiinflammatory therapy. 1293 49

The central melanocortin system plays an important role in the regulation of energy homeostasis both in rodents and humans, and melanocortin receptors appear to be the core of this system. Alpha-melanocyte-stimulating hormone (alpha-MSH) inhibits feeding through melanocrtin 3 and 4 receptors (MC3-R and MC4-R) as an endogenous agonist. Although mutations in the agouti gene cause an over-expression of agouti peptide which antagonizes effects of alpha-MSH at MC4-R in the brain and causes obese phenotypes, there was no evidence for the presence of an endogenous antagonist for MC3-R and MC4-R until agouti related protein (AGRP) was identified. AGRP is expressed primarily in the hypothalamic arcuate nucleus and central administration of AGRP stimulates feeding and weight gain, and decreases metabolic rate. Although a complete deletion of the AGRP gene does not produce any significant metabolic phenotypes, reduction in AGRP expression by RNA interference is associated with increased metabolic rate along with reduced weight gain. The currently available data suggest that elevated AGRP mRNA along with reduced proopiomelanocortin (POMC) mRNA is associated with many types of obesity and agents antagonizing the effect of AGRP may be a potential therapeutic target in treating obesity and obesity-associated disorders in which endogenous hypothalamic AGRP is elevated.
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PMID:The physiological function of the agouti-related peptide gene: the control of weight and metabolic rate. 1457 67

Mutations in the human melanocortin-4 receptor (MC4-R) gene may account for up to 5.8% of morbid nonsyndromic obesity. We have screened 120 unrelated obese patients for variants of the MC4-R gene. Four heterozygous missense variants were detected, including two polymorphisms (Val(103)Ile and Ile(251)Leu) previously described in the literature. A novel heterozygous mutation (Glu(308)Lys) was detected in a 36-yr-old female patient. Compared with the wild-type receptor, cells expressing the mutated receptor showed a reduced stimulation of cAMP production and a reduction of radioactive alpha MSH binding. No segregation of the mutation with the obese phenotype could be demonstrated. A second, potentially pathogenic mutation (Ser(30)Phe) was detected in a 31-yr-old female patient. Functional analysis of the mutated receptor showed no change in the affinity to the natural ligand alpha MSH nor limited ability to stimulate cAMP production. Sixty lean subjects were also screened, and no additional variants of the MC4-R gene were observed, except for two individuals with the Val(103)Ile polymorphism. In conclusion, we have screened a population of Italian obese subjects for MC4-R variants, demonstrating a 1.7% prevalence of potentially pathogenic mutations. A novel heterozygous missense mutation (Glu(308)Lys) that impairs MC4-R functional activity in vitro was characterized.
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PMID:Genetic screening for melanocortin-4 receptor mutations in a cohort of Italian obese patients: description and functional characterization of a novel mutation. 1476 12

Two Finnish cohorts, comprising 56 children with severe early-onset obesity (relative weight for height greater than or equal to +70% before age 10) and 252 morbidly obese adults (body mass index, > or = 40 kg/m(2)), were screened for melanocortin-4 receptor (MC4R) mutations. We identified a pathogenic mutation (S127L) in one child, causing severe early-onset obesity. We describe the phenotype of this particular mutation for the first time. We also identified a novel (I226T) polymorphism in the coding and two new variations (-439delGC and 1059C>T) outside the coding region of the MC4R gene. Three previously described polymorphisms (V103I, T112M, and I125L) were identified. In vitro functional studies of variants T112M, S127L, and I226T supported a pathogenic role of the S127L mutation, because signaling properties of the receptor in response to the MC4R agonists alpha-MSH, beta-MSH, and gamma(1)-MSH were impaired. The S127L mutation did not affect receptor inhibition by the antagonist agouti-related protein. Localization of the three variant receptors was similar to that of wild type. In conclusion, a pathogenic MC4R mutation was found among subjects with severe early-onset obesity but not among morbidly obese adults. Impaired function of the S127L receptor was due to reduced activation, not a defect of protein transport to the cell membrane.
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PMID:Identification and characterization of melanocortin-4 receptor gene mutations in morbidly obese finnish children and adults. 1476 18


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