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)

Several dominant mutations at the murine agouti locus cause a syndrome of marked obesity and insulin resistance. We have recently reported that intracellular free Ca2+ concentration ([Ca2+]i) is elevated in viable yellow mice. Because [Ca2+]i has a key role in the pathogenesis of insulin resistance, obesity, and hypertension, the role of the purified agouti gene product in regulating [Ca2+]i was evaluated in a number of cell types. Purified murine agouti induced slow, sustained increases in [Ca2+]i in A7r5 vascular smooth muscle cells and 3T3-L1 adipocytes in a dose-dependent fashion. In L6 skeletal myocytes, agouti stimulated an increase in [Ca2+]i with an apparent concentration eliciting 50% of the maximal response (EC50) of 62 nM. This response was substantially inhibited by Ca2+ entry blockade with nitrendipine. To determine whether melanocortin receptors play a role in agouti regulation of [Ca2+]i, we examined the effect of melanocortin peptides and agouti in cells stably transfected with human melanocortin receptors. Human embryonic kidney cells (HEK-293 cells) transfected with either the human melanocortin 1 receptor (MC1R) or melanocortin 3 receptor responded to human agouti with slow, sustained increases in [Ca2+]i, whereas nontransfected HEK-293 cells with no melanocortin receptors did not respond to agouti. Dose-response curves in the MC1R line showed that agouti had an EC50 of 18 nM, which is comparable to that for agouti antagonism of (125)I-Nle,D-Phe-alpha-melanocyte-stimulating hormone binding in the same cell line. This direct effect of agouti on stimulating increases in [Ca2+]i suggests a potential mechanism for agouti-induced insulin resistance.
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PMID:Agouti regulation of intracellular calcium: role of melanocortin receptors. 912 42

Cholecystokinin (CCK) is a 33-amino acid peptide with multiple functions in both the central nervous system (via CCK-B receptors) and the periphery (via CCK-A receptors). CCK mediation of satiety via the A-receptor subtype suggest a role for CCK in the management of obesity. The carboxy terminal octapeptide (CCK-8) is fully active in this regard, but is lacking in receptor selectivity, metabolic stability, and oral bioavailability. Inversion of the chirality of Asp7 in conjunction with N-methylation of Phe8 produces compound 5 which exhibits high affinity and 2100-fold selectivity for CCK-A receptors. Compound 6 (Hpa(SO3H)-Nle-Gly-Trp-Nle-MeAsp-Phe-NH2), derived from moving the N-methyl group from Phe to Asp, decreased CCK-B affinity substantially without affecting CCK-A affinity, giving a compound with 6600-fold selectivity for CCK-A receptors. These compounds inhibit food intake with nanomolar potency following intraperitoneal administration in fasted rats. In addition to greater potency, compound 6 produces weight loss in rats when administered over nine consecutive days. Intranasal administration of 6 potently inhibits feeding in beagle dogs. Compound 6 produces potent anorectic activity via the CCK-A receptor system.
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PMID:Synthesis and biological evaluation of potent, selective, hexapeptide CCK-A agonist anorectic agents. 943 99

Selective CCK-A agonist activity has been reported to induce satiety in a variety of animals, including man, and thereby suggests a therapeutic role for CCK in the management of obesity. To date, three general classes of CCK-A agonists have been reported, the full-length, sulfated hepta- and hexapeptides, a series of tetrapeptides, and most recently a series of benzodiazepines. The SAR of the hexa- and tetrapeptide classes suggests that the Hpa(SO(3)H) and Tac groups may not interact at the CCK-A receptor in the same location. However, the C-terminal dipeptide part of the hexapeptides and tetrapeptides appear to interact at the CCK-A receptor in a similar manner. Compound 7 (Hpa-Nle-Gly-Trp-Lys(Tac)-Asp-MePhe-NH(2)) derived from combining the features of the hexapeptides and the tetrapeptides has subnanomolar affinity and 3500-fold selectivity for CCK-A receptors. Compound 7 administered intraperitoneally produces potent, long-lasting reduction in food intake in rats and a corresponding weight loss when administered over nine consecutive days.
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PMID:CCK peptides with combined features of hexa- and tetrapeptide CCK-A agonists. 1088 60

The orphan receptor, bombesin (Bn) receptor subtype 3 (BRS-3), shares high homology with bombesin receptors (neuromedin B receptor (NMB-R) and gastrin-releasing peptide receptor (GRP-R)). This receptor is widely distributed in the central nervous system and gastrointestinal tract; target disruption leads to obesity, diabetes, and hypertension, however, its role in physiological and pathological processes remain unknown due to lack of selective ligands or identification of its natural ligand. We have recently discovered (Mantey, S. A., Weber, H. C., Sainz, E., Akeson, M., Ryan, R. R. Pradhan, T. K., Searles, R. P., Spindel, E. R., Battey, J. F., Coy, D. H., and Jensen, R. T. (1997) J. Biol. Chem. 272, 26062-26071) that [d-Tyr(6),beta-Ala(11),Phe(13),Nle(14)]Bn-(6-14) has high affinity for BRS-3 and using this ligand showed BRS-3 has a unique pharmacology with high affinity for no known natural Bn peptides. However, use of this ligand is limited because it has high affinity for all known Bn receptors. In the present study we have attempted to identify BRS-3 selective ligands using a strategy of rational peptide design with the substitution of conformationally restricted amino acids into the prototype ligand [d-Tyr(6),beta-Ala(11),Phe(13),Nle(14)]Bn-(6-14) or its d-Phe(6) analogue. Each of the 22 peptides synthesized had binding affinities determined for hBRS-3, hGRPR, and hNMBR, and hBRS-3 selective ligands were tested for their ability to activate phospholipase C and increase inositol phosphates ([(3)H]inositol phosphate). Using this approach we have identified a number of BRS-3 selective ligands. These ligands functioned as receptor agonists and their binding affinities were reflected in their potencies for altering [(3)H]inositol phosphate. Two peptides with an (R)- or (S)-amino-3-phenylpropionic acid substitution for beta-Ala(11) in the prototype ligand had the highest selectivity for the hBRS-3 over the mammalian Bn receptors and did not interact with receptors for other gastrointestinal hormones/neurotransmitters. Molecular modeling demonstrated these two selective BRS-3 ligands had a unique conformation of the position 11 beta-amino acid. This selectivity was of sufficient magnitude that these should be useful in explaining the role of hBRS-3 activation in obesity, glucose homeostasis, hypertension, and other physiological or pathological processes.
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PMID:Rational design of a peptide agonist that interacts selectively with the orphan receptor, bombesin receptor subtype 3. 1111 77

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

Loss-of-function mutations in the human melanocortin-4 receptor (MC4R) are associated with obesity. Previous work has implicated a C-terminal di-isoleucine motif at residues 316/317 in MC4R cell surface targeting. It was therefore of interest to examine function and cell surface expression of an MC4R mutation found in an obese proband in which one of these isoleucines was substituted by threonine (I317T). Single mutant (I316T or I317T) and double mutant (I316T,I317T) forms of MC4R were constructed by oligonucleotide-directed mutagenesis and tested for function and cell surface expression in transfected cells. Function was assessed using assays for agonist, [Nle(4)-d-Phe(7)]alpha-melanocyte-stimulating hormone (NDP-alpha-MSH) or forskolin-stimulated cAMP accumulation. Cell surface expression was determined by whole-cell binding of [(125)I]NDP-alpha-MSH, fluorescence immunocytochemistry and fluorescence-activated cell sorting. Maximal cAMP generation of the single mutants was reduced by 40% of wild-type receptor; the double mutant further reduced function to 40% of control, effects that were mirrored by decreases in cell-surface expression. Quantitative RT-PCR showed that, relative to wild-type receptor, transcript levels for the mutated receptors were not reduced. The results further implicate the C-terminal di-isoleucines in cell surface expression of MC4R and suggest that mutations of residues 316 or 317 would predict MC4R hypofunction.
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PMID:Cell surface expression of the melanocortin-4 receptor is dependent on a C-terminal di-isoleucine sequence at codons 316/317. 1259 26

Agouti-related protein (AGRP) is one of only two known endogenous antagonists of G-protein coupled receptors (GPCRs). Specifically, AGRP antagonizes the brain melanocortin-3 and -4 receptors involved in energy homeostasis, regulation of feeding behavior, and obesity. Alpha-melanocyte stimulating hormone (alpha-MSH) is one of the known endogenous agonists for these receptors. It has been hypothesized that the Arg-Phe-Phe (111-113) human AGRP amino acids may be mimicking the melanocortin agonist Phe-Arg-Trp (7-9) residue interactions with the melanocortin receptors that are important for both receptor molecular recognition and stimulation. To test this hypothesis, we generated thirteen chimeric peptide ligands based upon the melanocortin agonist peptides NDP-MSH (Ac-Ser-Tyr-Ser-Nle4-Glu-His-DPhe-Arg-Trp-Gly-Lys-Pro-Val-NH2) and MTII (Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2). In these chimeric ligands, the agonist DPhe-Arg-Trp amino acids were replaced by the AGRP Arg-Phe-Phe residues, and resulted in agonist activity at the mouse melanocortin receptors (mMC1R and mMC3-5Rs), supporting the hypothesis that the AGRP antagonist ligand Arg-Phe-Phe residues mimic the agonist Phe-Arg-Trp amino acids. Interestingly, the Ac-Ser-Tyr-Ser-Nle4-Glu-His-Arg-DPhe-Phe-Gly-Lys-Pro-Val-NH2 peptide possessed 7 nM mMC1R agonist potency, and is 850-fold selective for the mMC1R versus the mMC3R, 2300-fold selective for the mMC1R versus the mMC4R, and 60-fold selective for the MC1R versus the mMC5R, resulting in the discovery of a new peptide template for the design of melanocortin receptor selective ligands.
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PMID:Chimeric NDP-MSH and MTII melanocortin peptides with agouti-related protein (AGRP) Arg-Phe-Phe amino acids possess agonist melanocortin receptor activity. 1512 41

Agonists of the melanocortin 4 (MC4) receptor have potential pharmaceutical benefit in the treatment of obesity and sexual dysfunction. In this study, we have compared the ability of a number of peptide and nonpeptide agonists to activate a FLAG-tagged human MC4 (FMC4) receptor, as measured by both cAMP accumulation and calcium mobilization using a fluorometric imaging plate reader (FLIPR). In addition, we have analyzed the ability of these agonists to cause receptor internalization, as measured by fluorescence-activated cell sorting analysis. The endogenous agonist alpha-melanocortin-stimulating hormone (alpha-MSH) increased cAMP accumulation, calcium mobilization, and receptor internalization in a dose-dependent manner in human embryonic kidney 293 cells expressing the FMC4 receptor. The activity of the other agonists varied considerably in these assays, and overall, the potency and intrinsic activity of the agonists in the cAMP accumulation assays did not correlate with their potency or intrinsic activity in either the FLIPR or receptor internalization assays. Agonists could be clearly separated into two functional classes based on their structure. Peptide agonists beta-MSH, des-acetyl-alpha-MSH, and [Nle(4), D-Phe(7)]-alpha-melanocortin-stimulating hormone exhibited 80 to 112% of the maximal alpha-MSH response in cAMP accumulation and 62 to 96% in FLIPR assays and were able to cause 75 to 118% of receptor internalization induced by alpha-MSH. Conversely, although the nonpeptide agonists exhibited 73 to 149% of the alpha-MSH response in the cAMP accumulation assays, they were significantly impaired in the FLIPR (7-40%) and receptor internalization (-5-38%) assays. These findings demonstrate an important difference in activation and internalization of the MC4 receptor by nonpeptide versus peptide agonists and provides evidence of agonist-specific conformational states.
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PMID:Functional selectivity of melanocortin 4 receptor peptide and nonpeptide agonists: evidence for ligand-specific conformational states. 1574 21

Mutations of the human melanocortin-4 receptor (hMC4R) have been previously identified to be the most common cause of monogenic human obesity. Specifically, mutations of the intracellular C terminus and the third intracellular loop of hMC4R have been reported to play an important role in human obesity. However, the molecular basis of these hMC4R intracellular segments in receptor function remains unclear. In this study, we utilized deletions and mutations of specific portions of the hMC4R to determine the molecular mechanism of both the C terminus and the third intracellular loop in receptor signaling. Our results indicate that deletions of the distal 25 (the entire C terminus), 22, 18, 17, 16, and 15 amino acids of the C terminus result in the complete loss of both [Nle(4)-d-Phe(7)]-alpha-melanocyte stimulating hormone (NDP-MSH) binding and NDP-MSH-mediated cAMP production. Deletion of the distal 14 amino acids of the C terminus significantly decreases both NDP-MSH binding affinity and potency, but deletion of the distal 13 amino acids of the C terminus does not affect NDP-MSH activity. Further analysis revealed that the proximal 12 amino acids of the C terminus are not only important for receptor signaling but also important for ligand binding. Our results also indicate that the third intracellular loop of the hMC4R is important for receptor signaling but not ligand binding. In summary, our findings suggest that the proximal region of the melanocortin-4 receptor (MC4R) C terminus is crucial not only for receptor signaling but also for ligand binding, while the third intracellular loop is important mainly for receptor signaling.
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PMID:Molecular mechanism of the intracellular segments of the melanocortin-4 receptor for NDP-MSH signaling. 1586 42

Leptin gains access to the central nervous system where it influences activity of neuronal networks involved in ingestive behavior, neuroendocrine activity, and metabolism. In particular, the brain melanocortin (MC) system is important in leptin signaling and maintenance of energy balance. Although leptin or MC receptor insensitivity has been proposed to be associated with obesity, the present study compared central leptin and MC receptor stimulation on some of the above-mentioned parameters and investigated whether these treatments predict proneness to diet-induced obesity (DIO) in outbred Wistar rats. Third-cerebroventricular administration of equi-anorexigenic doses of leptin and of the MC agonist melanotan-II caused comparable increases in plasma ACTH and corticosterone levels and c-Fos-labeling in approximately 70% of paraventricular hypothalamic (PVN) neuronal cell bodies containing CRH. This reinforces involvement of paraventricular CRH neurons in the short-term neuroendocrine and ingestive effects of leptin and melanocortins. In the DIO prediction study, anorexigenic efficacy of melanotan-II was not correlated with any parameter linked to DIO but was highly correlated with MC in situ binding (with labeled [Nle(4),D-Phe(7)]alpha-MSH) as well as CRH immunoreactivity in the PVN of DIO rats. This suggests intricate relationships among MC signaling, the CRH system, and ingestive behavior unrelated to DIO. In the same animals, leptin's anorexigenic efficacy was not correlated with PVN MC in situ binding or CRH immunoreactivity but correlated inversely to post-DIO plasma leptin, liver weight, and abdominal adiposity, the latter being correlated to insulin resistance. Thus, differences in leptin but not MC signaling might underlie DIO, visceral obesity, and insulin resistance.
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PMID:Reduced anorexigenic efficacy of leptin, but not of the melanocortin receptor agonist melanotan-II, predicts diet-induced obesity in rats. 1616 22


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