Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020505 (hyperphagia)
 6,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Agouti-related protein (Agrp) is present in rat and human hypothalamus and is structurally related to agouti protein. Overexpression of either of these proteins results in obesity. However the effect of exogenous Agrp and its in vivo interaction with alpha-melanocyte stimulating hormone (alphaMSH), the likely endogenous melanocortin 3 and 4 receptor (MC3-R and MC4-R) agonist, have not been demonstrated. We report that 1 nmol of Agrp(83-132), a C-terminal fragment of Agrp, when administered intracerebroventricularly (ICV) into rats, increased food intake over a 24-h period (23.0+/-1.4 g saline vs 32.9+/-2.3 g Agrp, p<0.05). The hyperphagia was similar to that seen when 1 nmol of the synthetic MC3-R and MC4-R antagonist SHU9119 was given i.c.v. (19.6+/-1.8 g saline vs 32.5+/-1.7 g SHU9119, p<0.001). Both Agrp(83-132) and SHU9119 blocked the reduction in 1-h food intake of i.c.v. alphaMSH at the beginning of the dark phase. This effect occurred independently of whether the antagonists were administered simultaneously, or nine hours prior, to the alphaMSH. We have also shown Agrp(83-132) is an antagonist at the MC3-R and MC4-R, with similar inhibition of cAMP activation to that previously reported for the full length peptide. In conclusion, Agrp(83-132) administered i.c.v. increases feeding with long lasting effects and is able to inhibit the action of alphaMSH. This interaction may be mediated by the MC3-R and/or MC4-R.
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PMID:A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo. 975 29

The mahogany (mg) locus originally was identified as a recessive suppressor of agouti, a locus encoding a skin peptide that modifies coat color by antagonizing the melanocyte-stimulating hormone receptor or MC1-R. Certain dominant alleles of agouti cause an obesity syndrome when ectopic expression of the peptide aberrantly antagonizes the MC4-R, a related melanocyte-stimulating hormone receptor expressed in hypothalamic circuitry and involved in the regulation of feeding behavior and metabolism. Recent work has demonstrated that mg, when homozygous, blocks not only the ability of agouti to induce a yellow coat color when expressed in the skin of the lethal yellow mouse (AY), but also the obesity resulting from ectopic expression of agouti in the brain. Detailed analysis of mg/mg AY/a animals, presented here, demonstrates that mg/mg blocks the obesity, hyperinsulinemia, and increased linear growth induced by ectopic expression of the agouti peptide. Remarkably, however, mg/mg did not reduce hyperphagia in the AY/a mouse. Furthermore, mg/mg induced hyperphagia and an increase in basal metabolic rate in the C57BL/6J mouse in the absence of AY. Consequently, although mahogany is broadly required for agouti peptide action, it also appears to be involved in the control of metabolic rate and feeding behavior independent of its suppression of agouti.
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PMID:Mahogany (mg) stimulates feeding and increases basal metabolic rate independent of its suppression of agouti. 977 May 50

We have examined the effects of underfeeding and obesity on the density of hypothalamic melanocortin MC3 and MC4 receptors (MC3-R and MC4-R, respectively), which may mediate the hypophagic effects of alpha-melanocyte-stimulating hormone (MSH) in the rat. MC3-R and MC4-R were measured by quantitative autoradiography in brain sections using 125I-labeled Nle4-D-Phe7-alpha-MSH (125I-NDP-MSH) and discriminated by masking MC3-R with excess unlabelled gamma2-MSH. High densities of MC4-R occurred in the ventromedial (VMH) and arcuate (ARC) nuclei, median eminence (ME), and medial habenular nucleus (MHb), with lower densities in the dorsomedial hypothalamus (DMH) and forebrain regions. MC3-R were confined to the VMH, ARC, and MHb. After 10-days of food restriction (14% weight loss), density of MC4-R was significantly increased by 20-65% in the VMH, ARC, ME, and DMH, with no changes elsewhere. Similarly, obese (fa/fa) Zucker rats showed 43-98% increases in MC4-R in the same regions. By contrast, rats with diet-induced obesity (18% heavier than controls) showed significantly decreased binding to MC4-R, especially in the VMH, ARC, and ME. MC3-R showed no significant alterations in any model. We suggest that increased density of MC4-R with food restriction and in obese Zucker rats reflects receptor upregulation secondary to decreased release of alpha-MSH, consistent with increased hunger in these models. Conversely, downregulation of MC4-R in diet-induced obesity may indicate increased alpha-MSH secretion in an attempt to limit overeating. This alpha-MSH/MC4-R system may be inhibited by leptin and/or insulin. MC3-R are not apparently involved in regulating feeding.
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PMID:Altered energy balance causes selective changes in melanocortin-4(MC4-R), but not melanocortin-3 (MC3-R), receptors in specific hypothalamic regions: further evidence that activation of MC4-R is a physiological inhibitor of feeding. 1033

Over 20 severely obese subjects in 11 independent kindreds have been reported to have pathogenic heterozygous mutations in the gene encoding the melanocortin 4 receptor (MC4R), making this the most common known monogenic cause of human obesity. To date, the detailed clinical phenotype of this dominantly inherited disorder has not been defined, and no homozygous subjects have been described. We determined the nucleotide sequence of the entire coding region of the MC4R gene in 243 subjects with severe, early-onset obesity. A novel two-base pair GT insertion in codon 279 was found in two unrelated subjects, and four novel missense mutations, N62S, R165Q, V253I, C271Y, and one mutation (T112M) reported previously were found in five subjects. N62S was found in homozygous form in five children with severe obesity from a consanguineous pedigree. All four heterozygous carriers were nonobese. Several features of the phenotype, e.g. hyperphagia, tendency toward tall stature, hyperinsulinemia, and preserved reproductive function, closely resemble those reported previously in Mc4r knock-out mice. In addition, a marked increase in bone mineral density was seen in all affected subjects. In transient transfection assays, the N62S mutant receptor showed a responsiveness to alphaMSH that was intermediate between the wild-type receptor and mutant receptors carrying nonsense and missense mutations associated with dominantly inherited obesity. Thus MC4R mutations result in a syndrome of hyperphagic obesity in humans that can present with either dominant or recessive patterns of inheritance.
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PMID:Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. 1090 33

We investigated the effects of continuous intracerebroventricular infusion of a melanocortin 4 receptor antagonist HS014 (cyclic [AcCys11, D-Nal14, Cys18, Asp-NH2(22)]beta-MSH-(11-22)) over 12 days and a subsequent 12-day recovery period on food intake, body weight and copulatory behavior in male rats. The results show that the food intake increased immediately after the start of the infusion of HS014 (0.16 nmol/h) and progressively increased thereafter. No tachyphylaxis was observed. When the infusion of HS014 was terminated, the food-intake levels dropped. The body weights of the rats had increased by 17% by the end of the study, compared with controls. During the recovery period, the body weight decreased towards the levels of the control rats. These results indicate that overeating and the subsequent increases in body weight caused by blockage of the melanocortin 4 (MC4) receptor are reversible when the blockage is ended. We also tested the copulatory behavior of vigorous male rats in the presence of female rats in estrous. We registered mount latency, the number of mounts, the intromission latency, the number of intromissions, the ejaculation latency and the post-ejaculatory interval three times during the study and also after acute administration of HS014 and alpha-MSH. The sexual behavior of the male rats was not affected. These results indicate that the MC receptors, in particular the MC4 receptor, may not be a major mediator of effects on copulatory behavior in male rats.
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PMID:Chronic melanocortin 4 receptor blockage causes obesity without influencing sexual behavior in male rats. 1092 31

The central melanocortin system has been demonstrated to play a pivotal role in energy homeostasis. Genetic disruption of this system causes obesity in both humans and mice. Previous experiments have shown that centrally-administered melanocortin agonists inhibit food intake and stimulate oxygen consumption. Here we report that centrally-administered melanocortin agonists also inhibit basal insulin release, and alter glucose tolerance. Furthermore, increased plasma insulin levels occur in the young lean MC4-R knockout (MC4-RKO) mouse, and impaired insulin tolerance takes place before the onset of detectable hyperphagia or obesity. These data suggest that the central melanocortin system regulates not only energy intake and expenditure, but also processes related to energy partitioning, as indicated by effects on insulin release and peripheral insulin responsiveness. Previous studies emphasize the role of excess adipose mass in the development of tissue insulin resistance, leading to type II diabetes. The data presented here show that defects in the central control of glucose homeostasis may be an additional factor in some types of obesity-associated type II diabetes.
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PMID:The central melanocortin system can directly regulate serum insulin levels. 1096 76

In response to moderately increased dietary fat content, melanocortin-4 receptor-null mutant (MC4R-/-) mice exhibit hyperphagia and accelerated weight gain compared to wild-type mice. An increased feed efficiency (weight gain/kcal consumed) argues that mechanisms in addition to hyperphagia are instrumental in causing weight gain. We report two specific defects in coordinating energy expenditure with food intake in MC4R-/- mice. Wild-type mice respond to an increase in the fat content of the diet by rapidly increasing diet-induced thermogenesis and by increasing physical activity, neither of which are observed in MC4R-/- mice. Leptin-deficient and MC3R-/- mice regulate metabolic rate similarly to wild-type mice in this protocol. Melanocortinergic pathways involving MC4-R-regulated neurons, which rapidly respond to signals not requiring changes in leptin, thus seem to be important in regulating metabolic and behavioral responses to dietary fat.
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PMID:Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat. 1136 41

Mutations in the melanocortin 4 receptor gene (MC4R) are the most common cause of monogenic human obesity. As part of our ongoing project entitled 'Turkish Obesity Genome Study' we determined the nucleotide sequence of the entire coding region of the MC4R gene in 40 morbidly obese subjects from independent families. Here we report a novel heterozygous mutation (N274S) in an adult female obese individual (age: 52 yrs, BMI 41.7 kg/m(2), height 158 cm, weight: 104 Kg). The sister of the index case (age: 55 yrs, height: 160 cm, weight: 110 Kg, BMI: 43 kg/m(2)) also carries the same mutation. Although both sisters were morbidly obese and hypertensive the index case had normal plasma insulin and fasting blood glucose levels whereas her sister had type 2 diabetes mellitus. No abnormalities of the reproductive function were present. Despite marked hyperphagia in childhood both sisters had a history of relatively diminished intensity of appetite after the age of 20. Of notice, index case was diagnosed to have cyclothymia whereas her sister was being treated for bipolar affective disorder. Detailed clinical evaluation revealed normal bone mineral density and serum calcium parameters as well as intact thyroid axis and hypothalamus-pituitary-adrenal axis in both patients. The human MC4-R deficient phenotype resembles the murine deficient state with regard to preserved reproductive function although hyperphagia, increased linear growth and absence of diabetes in mice are not observed in humans. Affected individuals have hyperphagia in childhood, which looses intensity later in life, and they also present with normal height and diabetes mellitus. Accumulating evidence indicate that melanocortin endocrine system or defective melanocortin signaling has inherently different characteristics in mice and humans resembling the variation observed with regard to leptin deficiency in both species.
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PMID:A novel melanocortin 4 receptor (MC4R) gene mutation associated with morbid obesity. 1144 23

Intracerebroventricular (ICV) injection of Agouti related protein (AgRP), an endogenous melanocortin 3 and 4 receptor (MC3/4-R) antagonist, produces a prolonged increase in food intake. To clarify the roles of the MC3-R and MC4-R in AgRP-induced hyperphagia, the feeding effect of AgRP (83-132) was compared with that of the selective MC4-R antagonist, JKC-363 (cyclic [Mpr11, D-Nal14, Cys18, Asp22-NH2]-beta-MSH11-22). Single ICV administration of AgRP (83-132) increased food intake for 48 h whilst ICV JKC-363 increased food intake for 8h. An increase in body weight at 24 and 48 h was observed following AgRP (83-132) but not JKC-363 treatment. These data suggest that the sustained orexigenic action of AgRP (83-132) may not be through MC4-R antagonism.
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PMID:Sustained orexigenic effect of Agouti related protein may be not mediated by the melanocortin 4 receptor. 1212 33

The melanocortin 4 receptor (MC4-R) plays a pivotal role in maintaining energy homeostasis in rodents and humans. For example, MC4-R deletion or mutation results in obesity, hyperphagia, and insulin resistance. Additionally, subsets of leptin-induced autonomic responses can be blocked by melanocortin receptor antagonism, suggesting that MC4-R-expressing neurons are downstream targets of leptin. However, the critical autonomic control sites expressing MC4-Rs are still unclear. In the present study, we systematically examined the distribution of MC4-R mRNA in the adult rat central nervous system, including the spinal cord, by using in situ hybridization histochemistry (ISHH) with a novel cRNA probe. Autonomic control sites expressing MC4-R mRNA in the hypothalamus included the anteroventral periventricular, ventromedial preoptic, median preoptic, paraventricular, dorsomedial, and arcuate nuclei. The subfornical organ, dorsal hypothalamic, perifornical, and posterior hypothalamic areas were also observed to express MC4-R mRNA. Within extrahypothalamic autonomic control sites, MC4-R-specific hybridization was evident in the infralimbic and insular cortices, bed nucleus of the stria terminalis, central nucleus of the amygdala, periaqueductal gray, lateral parabrachial nucleus, nucleus of the solitary tract, dorsal motor nucleus of the vagus (DMV), and intermediolateral nucleus of the spinal cord (IML). By using dual-label ISHH, we confirmed that the cells expressing MC4-R mRNA in the IML and DMV were autonomic preganglionic neurons as cells in both sites coexpressed choline acetyltransferase mRNA. The distribution of MC4-R mRNA is consistent with the proposed roles of central melanocortin systems in feeding and autonomic regulation.
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PMID:Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat. 1254 7


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