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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Heterozygous mutations in the coding sequence of the serpentine melanocortin 4 receptor (MC4R) are the most frequent genetic cause of severe human obesity. Since haploinsufficiency has been proposed as a causal mechanism of obesity associated with these mutations, reduction in gene transcription caused by mutations in the transcriptionally essential regions of the MC4R promoter may also be a cause of severe obesity in humans. To test this hypothesis we defined the minimal promoter region of the human MC4R and evaluated the extent of genetic variation in this region compared with the coding region in two cohorts of severely obese subjects. 5'RACE followed by functional promoter analysis in multiple cell lines indicates that an 80-bp region is essential for the transcriptional activity of the MC4R promoter. Systematic screening of 431 obese children and adults for mutations in the coding sequence and the minimal core promoter of MC4R reveals that genetic variation in the transcriptionally essential region of the MC4R promoter is not a significant cause of severe obesity in humans.
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PMID:The human MC4R promoter: characterization and role in obesity. 1463 62

To elucidate mechanisms of melanocortin action, we investigated the effects of a melanocortin receptor agonist (melanotetan II [MTII]) in lean C57BL/6J and obese (DIO, ob/ob, UCP1-DTA) mice. MTII administration (100 microg q.i.d. i.p.) for 24 h results in similar weight loss but a more pronounced decrease of food intake in DIO mice. After 4 and 8 days of MTII treatment, however, the reduction in both food intake and body weight is more pronounced in DIO mice than in lean mice. MTII administration for 24 h prevents food deprivation-induced alterations in hypothalamic neuropeptide Y (NPY) and liver adiponectin receptor 1 and adiponectin receptor 2 mRNA expression, but does not alter hypothalamic mRNA expression of melanocortin 4 receptor or adiponectin serum and mRNA expression levels. NPY and agouti gene-related protein (AgRP) mRNA expression after 8 days of MTII is increased to levels comparable to pair-fed mice. In summary, 1) MTII is an effective treatment for obesity and related metabolic defects in leptin-resistant (DIO, UCP1-DTA) and leptin-sensitive (ob/ob) mouse models of obesity; 2) the effects of MTII on food intake and body weight are more pronounced in DIO mice than in lean mice; 3) the tachyphylactic effect after prolonged MTII administration appears to be, at least in part, caused by a compensatory upregulation of NPY and AgRP mRNA levels, whereas decreasing leptin levels may play a very minor role in mediating tachyphylaxis; and 4) alterations in adiponectin receptor mRNA expression after fasting or MTII treatment may contribute to altered insulin sensitivity and needs to be studied further.
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PMID:Responsiveness to peripherally administered melanocortins in lean and obese mice. 1469 1

The melanocortin receptor type 4 (MC4-R) is involved in food intake and represents a potential target for the treatment of some forms of obesity. The fluorescent protein EGFP was fused to the wild-type or mutated coding sequence of the human MC4-R. After transfection in HEK 293, clones stably expressing hMC4-R-EGFP were selected. Wild-type chimeric hMC4-R was well addressed to the cell membrane as demonstrated using confocal microscopy and displayed the same pharmacological characteristics as native hMC4R. NDP-alpha MSH induced a time-dependent internalization of MC4-R that was partially prevented by AgRP. The two mutated chimeric receptors studied here (CTCT-deleted and C271A) showed a high alteration of their response to ligand and were retained inside the cells. In conclusion, we have developed a model of clones stably expressing EGFP-tagged-hMC4-R. This is the only such model available to date and it provides a useful tool to follow the trafficking of MC4-R inside living cells.
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PMID:Characterization of cell lines stably expressing human normal or mutated EGFP-tagged MC4R. 1511 80

The proband, a 9-year-old Hispanic female, presented with hair loss, strabismus, and weight gain. On magnetic resonance imaging (MRI) she was found to have severe primary hypothyroidism and a large pituitary mass. In addition, acanthosis nigricans, obesity, and hyperinsulinism were observed. Findings were similar in three of four siblings. Thyroid peroxidase antibodies were detected in the father and three of four siblings. Although all family members were obese, and hyperinsulinemia with high proinsulin and C-peptide was found in all except one sibling, only the mother and one child had overt type 2 diabetes mellitus. Because of the unusual association of autoimmune thyroid disease, insulin resistance and obesity rather than insulin deficiency, we searched for possible genetic abnormalities. The HLA haplotypes did not cosegregate with autoimmune thyroid disease or insulin resistance. Mutational analysis of known obesity genes was done. Leptin was not deficient, and sequencing of the proband's DNA showed no mutations in the perixisome proliferator activated receptor (PPAR)-gamma, PPAR-gamma(2), PPAR-alpha or melanocortin 4 receptor genes. Maternally inherited diabetes and deafness was ruled out since no mutations were found in mitochondria DNA. Insulin receptor antibodies were not detected. In conclusion, the remarkably high incidence of childhood autoimmune hypothyroidism, pituitary enlargement, insulin resistance and obesity in this family is not linked to known HLA types or known gene defects.
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PMID:Familial juvenile autoimmune hypothyroidism, pituitary enlargement, obesity, and insulin resistance. 1514 66

Heterozygous coding mutations in the melanocortin 4 receptor gene (MC4R) are the most common genetic causes of severe human obesity identified to date. To determine whether MC4R has a role in causing severe obesity in Pima Indians, we sequenced the coding region of this gene in 426 full-heritage, non-first-degree related, adult Pima Indians (300 severely obese and 126 nondiabetic nonobese control subjects). Three coding variations were detected as heterozygotes only in severely obese subjects. One variation, detected in three obese subjects, was a novel single-base insertion (A) at nucleotide 100, and it predicted a frameshift and premature STOP at codon 37. The second variant, detected in 10 obese subjects, predicted a previously identified arginine-to-glutamine substitution at codon 165, and the third variant, detected in one obese subject, predicted a novel glycine-to-serine substitution at codon 231. Three polymorphisms were also identified in the 5' untranslated region, but these variants were detected in both obese and lean subjects and had similar allele frequencies. We conclude that variations in MC4R may account for a small portion of obesity in Pima Indians, but they do not explain the overall high prevalence of obesity in this Native American population.
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PMID:Melanocortin 4 receptor gene variation is associated with severe obesity in Pima Indians. 1544 3

Mutations in the gene encoding the melanocortin 4 receptor (MC4R) are associated with the most common monogenic form of obesity. We examined 750 Danish men with juvenile-onset obesity (body mass index 33.3 +/- 2.4 kg/m(2)) and 706 control subjects (body mass index 21.4 +/- 2.1 kg/m(2)) for mutations in MC4R. A total of 14 different mutations were identified of which two, Ala219Val and Leu325Phe, were novel variants. The variant receptor, Leu325Phe, was unable to bind [Nle4,d-Phe7]-alphaMSH, whereas the Ala219Val variant showed a significantly impaired melanotan II induction of cAMP, compared with the wild-type receptor. The remaining 11 mutations have previously been reported, but selected MC4R variants were further characterized in vitro in the present study. A previously identified nonsense mutation, Tyr35stop, had a relatively high allele frequency (0.6%), suggesting a possible founder effect in the Danish population. This study shows a carrier frequency of 2.5% of pathogenic mutations in the MC4R gene in a population-based study of obese men. Thus, variation in this gene is the most common known specific genetic cause of obesity among Scandinavian men.
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PMID:Prevalence of mutations and functional analyses of melanocortin 4 receptor variants identified among 750 men with juvenile-onset obesity. 1548 53

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

The adipocyte hormone leptin binds to its receptors in hypothalamic neurons and decreases appetite and food consumption. Its effect on appetite is mediated by melanocortines (MC) that are derivative of proopiomelanocortin (POMK) and their receptor (MC4-R). The knock-out of POMC gene or MC4-R gene causes obesity in animals. However, the growth of the animals intensifies and their reproductive function does not cease. The paper covers consequences of mutations in genes responsible for leptin regulation of various functions.
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PMID:[The role of leptin and its peptide mediators in neurophysiology]. 1577 67

Adaptive thermogenesis represents one of the important homeostatic mechanisms by which the body maintains appropriate levels of stored energy and its core temperature. Dysregulation of adaptive thermogenesis promotes obesity. The central melanocortin system, in particular the melanocortin 4 receptor (MC4R) signaling pathway, influences the regulation of every aspect of energy balance, including thermogenesis, and plays a critical role in energy homeostasis in both rodent and man. This review will outline our current understanding of adaptive thermogenesis, focusing on the role of the central melanocortin pathway in the regulation of thermogenesis.
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PMID:Regulation of thermogenesis by the central melanocortin system. 1597 59


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