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 coexpressed with neuropeptide Y (NPY) in a population of neurons in the arcuate nucleus (ARC) of the hypothalamus and stimulates food intake for up to 7 days if injected intracerebroventricularly. The prolonged food intake stimulation does not seem to depend on continued competition at the melanocortin-4 receptor (MC4R), because the relatively specific MC4R agonist MTII regains its ability to suppress food intake 24 h after AgRP injection. Intracerebroventricular AgRP also stimulates c-Fos expression 24 h after injection in several brain areas, so the neurons exhibiting delayed Fos expression might be particularly important in feeding behavior. Thus we aimed to identify the neurochemical phenotype of some of these neurons in select hypothalamic areas, using double-label immunohistochemistry. AgRP-injected rats ingested significantly more chow (10.2 +/- 0.6 g) vs. saline controls (3.4 +/- 0.7 g) in the first 9 h (light phase) after injection. In the lateral hypothalamus (particularly the perifornical area) 23 h after injection, AgRP induced significantly more Fos vs. saline in orexin-A (OXA) neurons (25.6 +/- 4.9 vs. 4.8 +/- 3.1%), but not in melanin-concentrating hormone (MCH) or cocaine- and amphetamine-regulated transcript (CART) neurons. In the ARC, AgRP induced significantly more Fos in CART (40.6 +/- 5.9 vs. 13.4 +/- 1.8%) but not NPY neurons. In the paraventricular nucleus, there was no significant difference in Fos expression induced by AgRP vs. saline in oxytocin and CART neurons. We conclude that the long-lasting hyperphagia induced by AgRP is correlated with and possibly partially mediated by hyperactive OXA neurons in the lateral hypothalamus and CART neurons in the ARC, but not by NPY and MCH neurons. The substantial increase in light-phase food intake by AgRP supports a role for the arousing effects of OXA. Activation of CART neurons in the ARC (which likely coexpress proopiomelanocortin) could indicate attempts to activate counterregulatory decreases in food intake.
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PMID:Neurochemical phenotype of hypothalamic neurons showing Fos expression 23 h after intracranial AgRP. 1201 Jul 60

The central melanocortin system is involved in the regulation of food intake and body weight. In this study, we investigated the effect of a 4-week intracerebroventricular infusion of the melanocortin receptor agonist MT-II and the selective melanocortin-4 receptor antagonist HS024 on food intake and body weight homeostasis. The MT-II-treated rats ate less and lost considerably more weight than the control rats during the first week of treatment. During the second and third week, they gained weight and, by the end of the treatment period, the weight gain was similar to that of the control rats. The HS024 treatment caused hyperphagia and development of obesity during the entire period. Extensive accumulations of fat and a sixfold increase in leptin levels were observed in the HS024-treated rats, as compared with controls, after the 4-week period. Food conversion ratio, defined as body weight increase relative to weight of ingested food, was clearly increased in the HS024-treated rats, while it was lowered in the MT-II-treated rats compared with controls. The effect on food conversion ratio was transient, being greatest for both experimental groups during the first week and it was then attenuated to reach the level of controls at the end of the study. The results suggest that long-term injection of exogenous melanocortin receptor active substances may have an important transient effect on food conversion.
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PMID:Food conversion is transiently affected during 4-week chronic administration of melanocortin agonist and antagonist in rats. 1206 41

Previous studies on mice with melanocortin-4 receptor gene (MC4r) knockout have focused on obese adults. Because humans with functional MC4r mutations show early-onset obesity, we determined the onset of excessive fat deposition in 10- to 56-day-old mice, taking into account sex and litter influences. Total body fat content of MC4r-/- on day 35 and MC4r+/- on day 56 significantly exceeds that of MC4r+/+. Plasma leptin levels increase in proportion to fat mass. According to cumulative food intake and energy expenditure measurements from day 21 to 35, onset of excessive fat deposition in MC4r-/- is fueled by hyperphagia and counteracted partially by hypermetabolism. In 35- to 56-day-old mice, arcuate nucleus neuropeptide Y (NPY) mRNA decreases and pro-opiomelanocortin (POMC) mRNA increases with fat content and plasma leptin levels independently of genotype. Taking into account fat content by ANCOVA reveals, however, increases in both NPY mRNA and POMC mRNA due to melanocortin-4 receptor (MC4R) deficiency. We conclude that hyperphagia, not hypometabolism, is the primary disturbance initiating excessive fat deposition in MC4R-deficient mice at weaning and that the overall changes in NPY and POMC expression tend to antagonize the onset of excessive fat deposition.
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PMID:Hyperphagia, not hypometabolism, causes early onset obesity in melanocortin-4 receptor knockout mice. 1264 29

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

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

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

The importance of the central melanocortin system in the regulation of energy balance is highlighted by studies in transgenic animals and humans with defects in this system. Mice that are engineered to be deficient for the melanocortin-4 receptor (MC4R) or pro-opiomelanocortin (POMC) and those that overexpress agouti or agouti-related protein (AgRP) all have a characteristic obese phenotype typified by hyperphagia, increased linear growth, and metabolic defects. Similar attributes are seen in humans with haploinsufficiency of the MC4R. The central melanocortin system modulates energy homeostasis through the actions of the agonist, alpha-melanocyte-stimulating hormone (alpha-MSH), a POMC cleavage product, and the endogenous antagonist AgRP on the MC3R and MC4R. POMC is expressed at only two locations in the brain: the arcuate nucleus of the hypothalamus (ARC) and the nucleus of the tractus solitarius (NTS) of the brainstem. This chapter will discuss these two populations of POMC neurons and their contribution to energy homeostasis. We will examine the involvement of the central melanocortin system in the incorporation of information from the adipostatic hormone leptin and acute hunger and satiety factors such as peptide YY (PYY(3-36)) and ghrelin via a neuronal network involving POMC/cocaine and amphetamine-related transcript (CART) and neuropeptide Y (NPY)/AgRP neurons. We will discuss evidence for the existence of a similar network of neurons in the NTS and propose a model by which this information from the ARC and NTS centers may be integrated directly or via adipostatic centers such as the paraventricular nucleus of the hypothalamus (PVH).
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PMID:The central melanocortin system and the integration of short- and long-term regulators of energy homeostasis. 1474 11

The melanocortin system is involved in hypothalamic regulation of energy homeostasis. The melanocortin-4 receptor (MC4R) has been linked to both obesity and reproductive dysfunction. Deletion of the MC4R from the mouse genome has resulted in phenotypes including adult onset obesity, hyperphagia, and difficulty in reproducing when homozygote parents are bred. Additionally, polymorphisms of the human MC4R have been identified in morbidly obese children and adults. Herein, we have identified that voluntary exercise, provided via the presence of a running wheel, impedes the monogenetic obesity (at 20 weeks of age running wheel housed body weight=31+/-1.8 g versus conventionally housed body weight=41+/-2.3 g, a 25% decrease in body weight p<0.01), hyperphagia (average cumulative food intake is not statistically different than wild type mice housed in running wheel cages), and reproductive dysfunction phenotypes associated with the MC4R knockout mice housed by conventional means. These data demonstrate the novel finding that voluntary exercise at a young age may hinder genetically induced obesity.
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PMID:Voluntary exercise delays monogenetic obesity and overcomes reproductive dysfunction of the melanocortin-4 receptor knockout mouse. 1559 47

Mutations of the melanocortin-4 receptor (MC4R) are associated with hyperphagia, obesity, and accelerated longitudinal growth in pig, mice and human. However, little is known about the functions of this gene in chicken. To map the MC4R gene in Chicken chromosome, we used a 6000 rads chicken-hamster radiation hybrid panel (ChikenRH6). PCR of samples from the ChikenRH6 revealed the location of the MC4R gene to be nearby markers MCW0062, BCL2 and OVY on chromosome 2q12. Five markers were placed into a single linkage group based on two-point analysis with a LOD score of greater than 5. At the same time, the MC4R gene was selected as marker to compare DNA sequence between chicken and human chromosome. The result shows there are the same homologous regions between chicken chromosome 2 (GGA2) and human chromosome 18 (HSA18), and we found that the genes BCL2 and obesity are located in the near regions of MC4R on human chromosome 18. So we can reduce that the chicken MC4R gene maybe there are the same functions with the human MC4R gene. Overall, this work reveals widespread chromosome rearrangements of MC4R between chicken and human genomes, and mappings the chicken MC4R gene on 2q12 by a RH panel.
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PMID:[Chromosomal mapping of chicken MC4R using a radiation hybrid panel and the comparative analysis of the gene homologous regions between chicken and human chromosome]. 1563 40

The melanocortin pathway consists of endogenous agonists, antagonists, G-protein coupled receptors, and ancillary proteins that mediate the function of the endogenous antagonists. The melanocortin-4 receptor (MC4R) is involved in the regulation of obesity and the melanocortin-2 receptor (MC2R) is involved in the regulation of steroidogenesis. Herein, we present the effects of voluntary exercise on the MC4R knockout mice in terms of bypassing the morbid obesity and hyperphagia phenotypes associated with this genetic obesity model. Additionally, a systematic truncation study of the adrenocorticotropin hormone (ACTH 1-24) has been performed and characterized at the cloned MC2R.
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PMID:The melanocortin pathway: effects of voluntary exercise on the melanocortin-4 receptor knockout mice and ACTH(1-24) ligand structure activity relationships at the melanocortin-2 receptor. 1566 96


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