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)

The melanocortin-4 receptor (MC4R) is critically involved in regulating energy balance, and obesity has been observed in mice with mutations in the gene for brain-derived neurotrophic factor (BDNF). Here we report that BDNF is expressed at high levels in the ventromedial hypothalamus (VMH) where its expression is regulated by nutritional state and by MC4R signaling. In addition, similar to MC4R mutants, mouse mutants that expresses the BDNF receptor TrkB at a quarter of the normal amount showed hyperphagia and excessive weight gain on higher-fat diets. Furthermore, BDNF infusion into the brain suppressed the hyperphagia and excessive weight gain observed on higher-fat diets in mice with deficient MC4R signaling. These results show that MC4R signaling controls BDNF expression in the VMH and support the hypothesis that BDNF is an important effector through which MC4R signaling controls energy balance.
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PMID:Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. 1283 Jan 51

Recent biological advances make it possible to discover new peptides associated with obesity. Leptin, neuropeptide Y, corticotrophin-releasing factor (CRF), alpha-melanocyte stimulating hormone (alpha-MSH), and cocaine- and amphetamine-regulated transcript (CART) peptides are known to participate in appetite and feeding behavior. Various lines of evidence suggest that these peptides participate not only in feeding behavior but also in cardiovascular and sympathetic regulations. Both leptin and ghrelin are secreted from the peripheral tissue; then they reach the brain to modulate sympathetic activity. These two peptides seem to play important roles to transmit peripheral metabolic information to the brain, and to convert it to cardiovascular and sympathetic information. Leptin activates neurons containing alpha-melanocyte stimulating hormone and cocaine- and amphetamine-regulated transcript peptides, resulting in increases in sympathetic activity and blood pressure. Cardiovascular action of alpha-melanocyte stimulating hormone is mediated through melanocortin-4 receptor, and agouti-related protein (AGRP) plays a role as an endogenous melanocortin-4 receptor antagonist. In contrast, ghrelin and neuropeptide Y in the brain suppress sympathetic activity and decrease blood pressure. Depressor and sympathoinhibitory effects of central neuropeptide Y are inhibited by leptin. Furthermore, central ghrelin modulates baroreflex control of renal sympathetic nerve activity and heart rate. Thus, leptin and the related peptides, which participate in appetite and feeding behavior, seem to function together to regulate cardiovascular system and sympathetic nerve activity, and may play a key role in the association between obesity and hypertension.
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PMID:Neural regulation of blood pressure by leptin and the related peptides. 1283 94

Chronic antagonism of hypothalamic melanocortin receptors, primarily melanocortin-4 receptor (MC4R), is the molecular basis for "agouti obesity syndrome," whereas suppression of MC4R gene activity due to genetic mutations induces obesity in both rodents and humans. However, little is known about the neurocircuitry of MC4R-mediated control of energy balance, the regulation of MC4R gene expression, or how suppression of MC4R activity leads to differential expression of potential downstream central nervous system (CNS) targets or effectors of melanocortin signaling. This paper focuses on strategies for mapping CNS melanocortin circuits using transgenic mouse models for conditional expression of MC4R and MC3R as well as progress in characterizing the murine MC4R promoter. Additionally, preliminary studies that focus on putative targets of melanocortinergic signaling will include a discussion of CD81, a gene identified using the polymerase chain reaction-based method of suppression subtractive hybridization. CD81, first described as TAPA-1 (target of antiproliferative antibody), is a member of the tetraspanin family of cell surface proteins believed to function in cell-cell adhesion, signal transduction, and possibly neuronal plasticity. Elevated expression of CD81 mRNA in hypothalamic regions of obese yellow mice suggests that loss of MC4R activity may lead to altered neuronal function via modulation of the cell surface protein CD81.
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PMID:Putative targets of CNS melanocortin receptor activity. 1285 18

Data from both rodent models and humans suggest that intact neuronal melanocortin signaling is essential to prevent obesity, as mutations that decrease the melanocortin signal within the brain induce hyperphagia and excess body fat accumulation. Melanocortins are also involved in the pathogenesis of disorders at the opposite end of the spectrum of energy homeostasis, the anorexia and weight loss associated with inflammatory and neoplastic disease processes. Studies using melanocortin antagonists (SHU9119 or agouti-related peptide) or genetic approaches (melanocortin-4 receptor null mice) suggest that intact melanocortin tone is required for anorexia and weight loss induced by injected lipopolysaccharide (an inflammatory gram-negative bacterial cell wall product) or by implantation of prostate or lung cancer cells. Although the precise mechanism whereby peripheral inflammatory/neoplastic factors activate the melanocortin system remains unknown, the proinflammatory cytokines (interleukin-1, interleukin-6, and tumor necrosis factor-alpha) that are produced in the hypothalamus of rodents during both inflammatory and neoplastic disease processes likely play a role. The data presented in this paper summarize findings that implicate neuronal melanocortin signaling in inflammatory anorexia.
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PMID:Melanocortin signaling and anorexia in chronic disease states. 1285 26

Within the past decade the molecular basis of single forms of monogenic obesity has been elucidated. With the exception of functionally relevant mutations in the melanocortin-4 receptor gene, which occur in approximately 2-4% of extremely obese individuals, all other currently known monogenic forms are rare and additionally associated with distinct endocrinological abnormalities. A large number of association studies have been performed in 'normal' obesity. Whereas many associations have been reported, it is largely unclear which of these represent true positive findings. Over 20 genome scans pertaining to obesity and related phenotypes have been performed; specific chromosomal peak regions have been identified in different scans. We review the current status and discuss relevant issues related to phenotyping, association and linkage studies. We recommend that the procedure via which a consensus is reached as to what constitutes a true positive association finding requires formalization.
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PMID:Perspectives: molecular genetic research in human obesity. 1291 15

The melanocortin-4 receptor (MC4R) is a member of the rhodopsin-like G protein-coupled receptor family. The binding of alpha-MSH to the MC4R leads to increased cAMP production. Recent pharmacological and genetic studies have provided compelling evidence that MC4R is an important regulator of food intake and energy homeostasis. Allelic variants of MC4R were reported in some children with early-onset severe obesity. However, few studies have been performed to confirm that these allelic variants result in an impairment of the receptor's function. In this study, we expressed wild-type and variant MC4Rs in HEK293 cells and systematically studied ligand binding, agonist-stimulated cAMP, and cell surface expression. Six of the 11 mutants examined had either decreased (S58C, N62S, Y157S, C271Y) or no (P78L, G98R) ligand binding, with proportional impairments in [Nle4, d-Phe7]-alpha-MSH-stimulated cAMP production. Confocal microscopy confirmed that the observed decreases in hormone binding by these mutants are associated with decreased cell surface expression due to intracellular retention of the mutants. The other five allelic variants (D37V, P48S, V50M, I170V, N274S) were found to be expressed at the cell surface and to bind agonist and respond with increased cAMP production normally. The data on these latter five variants raise the question as to whether they are indeed causative of the obesity or not and, if so, by what mechanism. Our data, therefore, stress the importance of characterizing the properties of MC4R variants associated with early-onset severe obesity. We further propose a classification scheme for mutant MC4Rs based upon their properties.
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PMID:Functional characterization of melanocortin-4 receptor mutations associated with childhood obesity. 1295 94

Mutations in the melanocortin-4 receptor (MC4R) are associated with obesity. The obesity syndrome observed in humans with MC4R haploinsufficiency is similar to that observed in MC4R knockout mice, including increased longitudinal growth, hyperphagia, and fasting hyperinsulinemia. For comparison with other commonly investigated models of obesity and insulin resistance, we have backcrossed Mc4r-/- mice into the C57BL/6J (B6) background. Female obese Mc4r-/- mice exhibit reduced energy expenditure and an attenuated increase in fatty acid (FA) oxidation after exposure to high-fat diets compared with obese Lepob/Lepob mice. The reduced energy expenditure and FA oxidation correlates with changes in hepatic gene expression. The expression of genes involved in FA oxidation increased in obese Lepob/Lepob mice compared with wild-type and obese Mc4r-/- mice. In contrast, a key lipogenic enzyme, FA synthase (FAS), is increased in obese Mc4r-/- mice compared with obese Lepob/Lepob mice. Hyperinsulinemia, increased FAS mRNA expression and hepatic steatosis appear to be secondary to obesity in B6 Mc4r-/- mice. However, Mc4r-/- mice in a mixed genetic background develop severe hepatic steatosis at an early age. This might suggest an important role of the MC4R in regulating liver FA metabolism that is masked on the B6 background. Interestingly, the 10- to 20-fold increase in liver triglyceride in the outbred strain of Mc4r-/- mice is not always associated with fasting hyperinsulinemia or increased FAS mRNA expression. This observation suggests that changes in liver secondary to triglyceride accumulation lead to hyperinsulinemia and increased hepatic FAS expression in Mc4r-/- mice.
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PMID:Impaired coordination of nutrient intake and substrate oxidation in melanocortin-4 receptor knockout mice. 1455 Dec 22

Mutations in the melanocortin-4 receptor (MC4R) gene are the most frequent monogenic causes of severe obesity. Most mutations have been described as heterozygous with loss of function, suggesting that haploinsufficiency is the most likely mechanism of dominant inheritance. We detected a heterozygous mutation, D90N, in a patient with severe early-onset obesity. Functional characterization of the mutant receptor revealed normal cell-surface expression and binding properties but loss of signal transduction activity. In coexpression studies of wild-type (WT)-MC4R and D90N, the mutant receptor had a dominant-negative effect on WT-receptor function. Further investigation of this effect with sandwich enzyme-linked immunosorbent assays and fluorescence resonance energy transfer studies showed that the WT-MC4R and the D90N mutant form homodimers and heterodimers. We hypothesize that the dominant-negative effect of the D90N mutation is caused by a functionally altered WT-MC4R/D90N receptor heterodimer. These findings necessitate the reinvestigation of other heterozygous MC4R missense mutations to discriminate between haploinsufficiency and a dominant-negative effect. The finding of receptor dimerization highlights a more complex hypothalamic signaling network governing the regulation of body weight.
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PMID:Autosomal-dominant mode of inheritance of a melanocortin-4 receptor mutation in a patient with severe early-onset obesity is due to a dominant-negative effect caused by receptor dimerization. 1463 60

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

Anorexia is one of the common symptoms caused by various psychiatric disorders. Increasing evidence indicates that neuroleptics can induce weight gain, obesity, and diabetes mellitus. However, the mechanisms underlying these conditions have not been fully elucidated. In this review, we describe molecular neuroanatomic aspects of current biology of energy homeostasis that would help to address the psychiatric issues noted above, focusing on the central leptin/melanocortin system. An adipocyte-derived hormone, leptin acts on the arcuate hypothalamic nucleus (Arc) to inhibit feeding behavior and simultaneously to promote energy expenditure. Leptin activates Arc neurons producing alpha-melanocyte-stimulating hormone (alpha-MSH) and inhibits those producing agouti-related protein (AgRP). alpha-MSH is an endogenous agonist for the melanocortin-4 receptor (MC4-R) that is expressed exclusively in the central nervous system (CNS), whereas AgRP acts as a MC4-R antagonist. It is also established that MC4-R blockade produces an over-eating/obesity syndrome in rodents and humans. Thus, MC4-R-expressing neurons are downstream targets of leptin. Of interest, MC4-R-positive neurons densely populate in CNS sites critical for energy homeostasis and associated with psychiatric disorders, including the paraventricular hypothalamic nucleus and central amygdaloid nucleus. In addition, Arc alpha-MSH neurons receive serotonergic inputs from raphe neurons. Finally, an AgRP gene polymorphism has been associated with anorexia nervosa. These findings suggest that the central melanocortin system is a target for psychiatry.
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PMID:[Psychiatric disorders and neural mechanisms underlying energy intake and expenditure: a review]. 1465 25


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