Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Agouti-related protein (AGRP) is one of two known naturally occurring antagonists of G-protein coupled receptors. AGRP is synthesized in the brain and is an antagonist of the melanocortin-3 and -4 receptors (MC3R, MC4R). These three proteins are involved in the regulation of energy homeostasis and obesity in both mice and humans. The human AGRP protein is 132 amino acids and contains five disulfide bridges in the C-terminal domain. Previous reports of the NMR structures of hAGRP(87-132) and a truncated 34 amino acid form consisting of four disulfide bridges identified that AGRP contains an inhibitor cystine knot (ICK) structural fold, and that is the first mammalian example. Herein, we report a bicyclic hAGRP analogue that, when compared to hAGRP(87-132), possesses equal binding affinity but is 80-fold less potent at the mouse MC4R. Using NMR, computer assisted molecular modeling (CAMM), and cluster analysis, we have identified five structural families, two of which are highly populated, of this bicyclic hAGRP analogue. Computational docking experiments of this bicyclic hAGRP derivative, using a three-dimensional homology molecular model of the mouse MC4R, identified that three of the five structural families could be docked into the MC4R without problems from steric hindrance. Those three docked mMC4R-bicyclic hAGRP family structures were compared with putative hAGRP(87-132) ligand-receptor interactions previously reported (Wilczynski et al. J. Med. Chem. 2004, 47, 2194) in attempts to identify a "bioactive" conformation of the bicyclic hAGRP peptide and account for the 80-fold decreased ligand potency compared to hAGRP(87-132).
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PMID:Structural characterization and pharmacology of a potent (Cys101-Cys119, Cys110-Cys117) bicyclic agouti-related protein (AGRP) melanocortin receptor antagonist. 1550 65

Obesity-related phenotypes have been linked to human chromosomes 1q21 and 20q13, regions where the lamin A/C gene (LMNA) and the melanocortin 3 receptor gene (MC3R) map, respectively. Recently, a common single nucleotide polymorphism (SNP) in LMNA (1908C/T) was associated with plasma leptin and obesity indices in aboriginal Canadians, but these associations have not yet been explored in other populations. In contrast, no significant associations of MC3R variants with obesity have been detected, although a significant association with hyperinsulinemia has been reported in Caucasian populations. We investigated the associations between the LMNA 1908C/T variant and the 241G/A variant of the MC3R gene (Val81Ile missense mutation) and body composition, as well as plasma leptin and insulin levels, in two samples of unrelated healthy Greek subjects. A group of 112 young nonobese subjects, and a group of 116 adult women with a body mass index (BMI) ranging from 23.2 to 47.7 kg/m2 were studied cross-sectionally. We found no significant association of the LMNA 1908C/T and a borderline significant association of MC3R 241G/A SNPs with body composition variables, in the entire study sample. However, unlike the LMNA 1908C/T genetic variation, the MC3R 241G/A genetic variation was significantly associated with hyperleptinemia and huperinsulinemia in obese subjects, and there was evidence of interaction between this polymorphism and fat mass or BMI in predicting hyperinsulinemia. Our results suggest that the LMNA 1908C-->T substitution and the Val81Ile mutation of the MC3R gene are unlikely to be major predictors of body composition in Greek Caucasians, but the latter genetic variation may predispose obese subjects to develop insulin and leptin resistance. Future studies are needed to confirm these data and assess whether individuals carrying this mutation are more resistant to weight-reducing and insulin-sensitizing treatments.
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PMID:The Val81 missense mutation of the melanocortin 3 receptor gene, but not the 1908c/T nucleotide polymorphism in lamin A/C gene, is associated with hyperleptinemia and hyperinsulinemia in obese Greek caucasians. 1563 22

Genetic knockout and null mutations of melanocortin system components lead to phenotypes that recapitulate the metabolic syndrome such as obesity, hypertension and insulin resistance. Since stress is known to modify metabolic and cardiovascular function, we hypothesized the involvement of the neural melanocortin system in the stress response. Male rats were subjected to rapid-eye-movement sleep deprivation stress and the levels of proopiomelanocortin (POMC), MC3R, MC4R and MC5R transcripts in the hypothalamic-pituitary-adrenal axis (HPA) determined by real-time PCR. Increased levels of POMC transcripts were observed in the hypothalamus and adrenal gland tissues but there were no significant changes in the expression of the receptors genes. Whereas MC3R and MC5R are expressed in all HPA tissues, MC4R seems to be restricted mainly to the hypothalamus. It is possible that melanocortin receptors function in different aspects of the neuron. In vitro studies showed similar cellular distribution patterns for MC3R and MC4R and sequence analyses revealed strong conservation of the putative G-protein coupled receptors (GPCR) C-terminal membrane localization signal, EX(3-7)II/L motif, in MC3R, MC4R and MC5R. These data suggest that the physiological roles of neural melanocortin receptors, MC3R and MC4R, are likely determined by distinct tissue distribution patterns and suggest a role for hypothalamic and intra-adrenal melanocortin systems in the manifestation of stress related pathologies.
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PMID:Neural melanocortin receptors are differentially expressed and regulated by stress in rat hypothalamic-pituitary-adrenal axis. 1564 Nov 61

To evaluate whether MTII, a melanocortin receptor 3/4 agonist, is working in hypophagic and hypothermogenic obese model, we measured food intake, body weight, oxygen consumption, and fat mass following intracerebroventricular (i.c.v.) infusion of MTII in monosodium glutamate (MSG)-induced obese rats. MTII, or artificial cerebrospinal fluid (aCSF), was infused into i.c.v. with an osmotic minipump for 1 week. MSG-obese rats were induced by neonatal injection of MSG. Five-month-old MSG rats were characterized by hypophagia, lower oxygen consumption, hyperleptinemia, and obesity compared to age-matched control rats. The infusion of MTII decreased their food intake, visceral fat, and body weight in MSG-obese rats compared with aCSF-infused rats. The oxygen consumption was increased by MTII treatment in MSG-obese rats compared with aCSF as well as pair fed (PF) rats. Interestingly, these leptin-like effects of MTII were greater in MSG-obese rats than in controls, which might be related to the increased expression of melanocortin receptor 4 (MC4R) in the hypothalamus of MSG-obese rats. Our results suggested that both anorexic and thermogenic mechanisms were activated by MTII in the MSG-obese rats and contributed to the decrease in body weight and fat mass. Moreover, there was a sensitization to MTII caused by upregulation of the melanocortin receptor in the MSG-obese rats.
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PMID:Leptin-like effects of MTII are augmented in MSG-obese rats. 1568 Apr 71

Obesity is increasing in severity and prevalence in the United States and represents a major public health issue. No effective pharmacologic treatment leading to sustained weight loss currently exists. The growing interest in the regulation of food intake stems from the current drug treatments for obesity, almost all of which interfere with the monoamine system. Our knowledge of potential interactions between the orexigenic and anorexigenic pathways is limited and fragmented, making the development of targeted drug therapy for obesity difficult. The present review of the interaction of neuropeptides and monoamines emphasizes the complexity of the central mechanisms that regulate feeding behavior. Two main systems are implicated in food intake regulation: neuropeptide Y (NPY) and pro-opiomelanocortin. alpha-Melanocyte-stimulating hormone is a tridecapeptide cleaved from pro-opiomelanocortin that acts to inhibit food intake. The predominant NPY orexigenic receptors are NPY-Y1 and NPY-Y5, and the two anorexigenic melanocortin receptors involved in hypothalamic food intake control are MC3-R and MC4-R. Both neuropeptides interact with monoamines in the hypothalamus to control physiologic states such as hunger, satiation, and satiety. Serotonin suppresses food intake and body weight, acting mainly through the serotonin 1B receptor. Dopamine regulates hunger and satiety by acting in specific hypothalamic areas, through the D1 and D2 receptors. Noradrenaline activation of alpha1- and beta2-adrenoceptors decreases food intake, and stimulation of the alpha2-adrenoceptor increases food intake. A better understanding of the detailed mechanisms underlying the pathogenesis of hyperphagia and hypophagia is needed to develop new therapeutic approaches to obesity.
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PMID:Neuropeptide Y, alpha-melanocyte-stimulating hormone, and monoamines in food intake regulation. 1572 58

Hypothalamic melanocortins are critical for the control of food intake, and alterations in POMC mRNA have been described in genetic models of obesity. However, the time course of changes in brain transmitters over the development of dietary obesity is less clear. Therefore, we examined the effect of diet-induced obesity on hypothalamic alpha-MSH content and feeding responsiveness to synthetic melanocortins. Male Sprague-Dawley rats fed a high-fat cafeteria diet (30% fat) or chow (5% fat) for 4 or 12 weeks were implanted with intracerebroventricular cannulae and feeding responses to the MC3/4R agonist MTII (0.5 nmol) and the selective MC4R antagonist HS014 (0.8 nmol) were determined. MTII had a long-lasting inhibitory effect on food intake. Chronically overfed animals had a significantly exaggerated inhibitory feeding response 15 and 24 h after MTII injection and lost more body weight (15 +/- 3 g) compared to control rats (4 +/- 4 g; P < 0.05). Daytime administration of HS014 significantly increased food intake in all rats to the same extent (P < 0.05). No change in hypothalamic alpha-MSH content was observed after 2 or 12 weeks of high-fat diet. The observation of increased responsiveness to the melanocortin agonist, in the face of a high-fat diet, suggests melanocortin analogues may have potential for the pharmacological treatment of obesity.
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PMID:Feeding responses to a melanocortin agonist and antagonist in obesity induced by a palatable high-fat diet. 1578 Oct 55

The MC3R and MC4R proteins comprise two melanocortin receptor subtypes that are involved in obesity, with each protein displaying a unique mechanism of action. To enable the design of a selective drug candidate, the solution structures of four peptidyl analogues of the melanocyte stimulating hormones, NDP-MSH, NDP-MSH(4-10) and two cyclic forms ([C5,C10]NDP-MSH(5-10), [C5,C10]NDP-MSH(5-11)), were characterized by two-dimensional nuclear magnetic resonance (NMR) spectroscopy and simulated annealing calculations. Using data from c-AMP assays in combination with structural analysis of melanocortin receptor/ligand models, we conclude that a lysine residue at the C-terminus of the His-Phe-Arg-Trp core sequence of melanocortin hormone is an important determinant for receptor selectivity in the both cyclic and linear MSH analogues. Our results suggest that side-chain orientation and charge-charge interactions with the ligand molecule play critical roles in receptor selectivity, whereas the overall backbone conformation or turn type contributes mainly to receptor binding.
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PMID:Structure and function of the potent cyclic and linear melanocortin analogues. 1589 Feb 78

The neural melanocortin receptors, melanocortin-3 and -4 receptors (MC3R and MC4R), have been shown to regulate different aspects of energy homeostasis in rodents. Human genetic studies showed that mutations in the MC4R gene are the most common monogenic form of obesity. Functional analyses of the mutant receptors revealed multiple defects. A classification scheme is presented for cataloguing the ever-increasing array of MC4R mutations. Functional analysis of the only inactivating MC3R mutation is also summarized. Insights from the analyses of the naturally occurring mutations in the MC3R and MC4R on the structure and function of these receptors are highlighted.
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PMID:Molecular mechanisms of the neural melanocortin receptor dysfunction in severe early onset obesity. 1597 5

Ghrelin stimulates food intake in part by activating hypothalamic neuropeptide Y (NPY) neurons/agouti related peptide (AGRP) neurons. We investigated the role of AGRP/melanocortin signaling in ghrelin-induced food intake by studying melanocortin 3 and 4 receptor knockout (MC3R KO and MC4R KO) mice. We also determined whether reduced ghrelin levels and/or an altered sensitivity to the GH-stimulating effects of ghrelin accompany the obesity syndromes of MC3R KO and MC4R KO mice. Compared to wild-type (WT) mice, the effects of ghrelin on food intake were reduced in MC3R KO and MC4R KO mice and circulating ghrelin levels were reduced in female MC4R KO mice. Female MC3R KO and MC4R KO mice exhibited a diminished responsiveness to the GH-releasing effects of ghrelin. Thus, deletion of the MC3R or MC4R results in a decreased sensitivity to ghrelin and verifies the involvement in the melanocortin system in ghrelin-induced food intake.
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PMID:Ghrelin-induced food intake and growth hormone secretion are altered in melanocortin 3 and 4 receptor knockout mice. 1600 45

Previous studies suggest that blockade of melanocortin 3 and 4 receptors (MC3/4-R) markedly attenuates the chronic hypertensive effects of leptin. Although obesity has been reported to be associated with leptin "resistance," it is unclear whether obesity alters the cardiovascular and metabolic effects of chronic MC3/4-R activation. Therefore, we tested whether the cardiovascular and metabolic actions of MC3/4-R activation are attenuated in Sprague-Dawley rats fed a high-fat diet (HF, n=6) compared with rats fed a standard chow (NF, n=6) for 12 months. A 21G steel cannula was placed in the lateral ventricle for ICV infusion, and arterial and venous catheters were implanted for measurement of mean arterial pressure (MAP) 24 hours/day and IV infusions. After a 5-day control period, rats were infused with MC3/4-R agonist melanotan II (10 ng/h, ICV), for 10 days followed by a 5-day recovery period. HF rats were heavier (558+/-21 versus 485+/-13 g) with 140% more visceral fat than NF rats, hyperleptinemic (8.9+/-0.5 versus 2.7+/-0.5 ng/mL), and insulin resistant. HF rats also had higher MAP (109+/-3 versus 100+/-1 mm Hg). Chronic melanotan II infusion significantly increased MAP in HF and NF (7+/-2 and 6+/-1 mm Hg), decreased caloric intake (-32+/-2 and -25 +/-2 kcal/day), and reduced insulin levels in both groups by approximately 50%. Thus, the metabolic and cardiovascular actions of chronic MC3/4-R activation are preserved in diet-induced obesity, supporting a potential role for the hypothalamic melanocortin system in obesity hypertension.
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PMID:Does obesity induce resistance to the long-term cardiovascular and metabolic actions of melanocortin 3/4 receptor activation? 1638 May 16


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