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

Dominant alleles at the agouti locus (A) cause an obesity syndrome in the mouse, as a consequence of ectopic expression of the agouti peptide. This peptide, normally only found in the skin, is a high-affinity antagonist of the melanocyte-stimulating hormone receptor (MC1-R), thus explaining the inhibitory effect of agouti on eumelanin pigment synthesis. The agouti peptide is also an antagonist of the hypothalamic melanocortin-4 receptor (MC4-R). To test the hypothesis that agouti causes obesity by antagonism of hypothalamic melanocortin receptors, we identified cyclic melanocortin analogues that are potent agonists or antagonists of the neural MC3 (refs 11, 12) and MC4 receptors. Intracerebroventricular administration of the agonist, MTII, inhibited feeding in four models of hyperphagia: fasted C57BL/6J, ob/ob, and A(Y) mice, and mice injected with neuropeptide Y. Co-administration of the specific melanocortin antagonist and agouti-mimetic SHU9119 completely blocked this inhibition. Furthermore, administration of SHU9119 significantly enhanced nocturnal feeding, or feeding stimulated by a prior fast. Our data show that melanocortinergic neurons exert a tonic inhibition of feeding behaviour. Chronic disruption of this inhibitory signal is a likely explanation of the agouti obesity syndrome.
 ...
PMID:Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. 899 Jan 9

The melanocortin-4 receptor (MC4-R) is a G protein-coupled, seven-transmembrane receptor expressed in the brain. Inactivation of this receptor by gene targeting results in mice that develop a maturity onset obesity syndrome associated with hyperphagia, hyperinsulinemia, and hyperglycemia. This syndrome recapitulates several of the characteristic features of the agouti obesity syndrome, which results from ectopic expression of agouti protein, a pigmentation factor normally expressed in the skin. Our data identify a novel signaling pathway in the mouse for body weight regulation and support a model in which the primary mechanism by which agouti induces obesity is chronic antagonism of the MC4-R.
 ...
PMID:Targeted disruption of the melanocortin-4 receptor results in obesity in mice. 901 99

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.
 ...
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 cloning of mouse obesity genes and their human homologues provides unique opportunities to identify novel cellular targets for therapeutic intervention. The first of these to be cloned, agouti, antagonizes central nervous system melanocortin receptor (MCR) binding, resulting in hyperphagia and an obesity/hyperinsulinemia syndrome. There appears to be significant cross-talk between the agouti and leptin signaling systems. Agouti antagonism of central nervous system (CNS) MCR binding inhibits the anorexic effects of leptin, whereas agouti up-regulates adipocyte leptin expression, serving to limit the magnitude of agouti-induced obesity. The effects of agouti and leptin mutations on obesity, however, are independent and additive. Agouti also regulates adipocyte lipid metabolism, functioning both to increase the expression and activity of lipogenic genes and to inhibit lipolysis. Both of these actions occur via a Ca(2+)-dependent mechanism, suggesting that modulation of adipocyte Ca2+ transport may be a key target for further investigation.
 ...
PMID:Agouti/melanocortin interactions with leptin pathways in obesity. 976 77

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.
 ...
PMID:Mahogany (mg) stimulates feeding and increases basal metabolic rate independent of its suppression of agouti. 977 May 50

Genetic obesity is associated with increased neuropeptide Y (NPY) messenger RNA (mRNA) and decreased POMC mRNA in the hypothalamus of ob/ob and db/db mice, or impaired sensitivity to alphaMSH (derived from POMC) in the yellow agouti mouse. Acquired obesity can be produced by chemically lesioning the hypothalamus with either monosodium glutamate (MSG) in neonates or gold thioglucose (GTG) in adult mice. The present study examined whether elevated NPY mRNA and/or decreased POMC mRNA in the hypothalamus are associated with obesity due to hypothalamic lesions. GTG injection into adult mice produced a profound obese phenotype, including hyperphagia, increased body weight, and increased leptin mRNA and peptide, in association with reduced hypothalamic NPY mRNA and POMC mRNA. MSG treatment produced virtual elimination of NPY mRNA in the arcuate nucleus and a reduction of hypothalamic POMC mRNA, and led to elevated leptin. MSG pretreatment did not attenuate GTG-induced hyperphagia and obese phenotype. These results do not support a role for NPY-synthesizing neurons in the arcuate nucleus in mediating hypothalamic acquired obesity, but are consistent with the hypothesis that decreased activity of hypothalamic neurons synthesizing POMC play a role in mediating hypothalamic obesity.
 ...
PMID:Hyperphagia and weight gain after gold-thioglucose: relation to hypothalamic neuropeptide Y and proopiomelanocortin. 979 56

Hypothalamic neuropeptides play critical roles in the regulation of feeding behavior and body weight (BW). Disruption of signaling in the ventromedial nucleus by microinjection of the neurotoxin, colchicine (COL), produces transient hyperphagia with corresponding BW gain lasting for 4 days. Because the melanocortin system exerts an inhibitory control on food intake, we hypothesized that hyperphagia in COL-treated rats is due to decreased melanocortin-induced restraint on feeding. Melanocortin restraint is exerted through alpha-melanocortin-stimulating hormone derived from proopiomelanocortin (POMC) and is antagonized by agouti-related peptide produced in neurons located in the arcuate nucleus (ARC). COL (4 microg/0.5 microl saline) or saline was microinjected bilaterally into the ventromedial nucleus of adult male rats. In conjunction with BW gain, blood leptin levels were elevated, whereas POMC mRNA in the ARC was significantly decreased in COL-injected rats. Levels of alpha-melanocortin-stimulating hormone were also decreased in the micropunched paraventricular nucleus, dorsomedial nucleus, and perifornical hypothalamus, sites implicated in the control of food intake. That diminution in melanocortin signaling underlies hyperphagia was supported by the observation that intracerebroventricular injection of the MC3/MC4 melanocortin receptor agonist, MTII, prevented the hyperphagia and BW gain. Surprisingly, however, mRNA levels of the orexigenic peptide agouti-related peptide in the ARC were decreased perhaps due to the action of elevated leptin. These results show that transient hyperphagia and BW gain induced by disruption of signaling in the ventromedial nucleus results from two neurochemical rearrangements: development of leptin resistance in POMC neurons and diminution in melanocortin signaling as reflected by decreased POMC gene expression in the ARC and decreased availability of alpha-melanocortin-stimulating hormone for release in feeding relevant sites.
 ...
PMID:Melanocortin signaling is decreased during neurotoxin-induced transient hyperphagia and increased body-weight gain. 1095 99

The hypothalamus is the focus of many peripheral signals and neural pathways that control energy homeostasis and body weight. Emphasis has moved away from anatomical concepts of 'feeding' and 'satiety' centres to the specific neurotransmitters that modulate feeding behaviour and energy expenditure. We have chosen three examples to illustrate the physiological roles of hypothalamic neurotransmitters and their potential as targets for the development of new drugs to treat obesity and other nutritional disorders. Neuropeptide Y (NPY) is expressed by neurones of the hypothalamic arcuate nucleus (ARC) that project to important appetite-regulating nuclei, including the paraventricular nucleus (PVN). NPY injected into the PVN is the most potent central appetite stimulant known, and also inhibits thermogenesis; repeated administration rapidly induces obesity. The ARC NPY neurones are stimulated by starvation, probably mediated by falls in circulating leptin and insulin (which both inhibit these neurones), and contribute to the increased hunger in this and other conditions of energy deficit. They therefore act homeostatically to correct negative energy balance. ARC NPY neurones also mediate hyperphagia and obesity in the ob/ob and db/db mice and fa/fa rat, in which leptin inhibition is lost through mutations affecting leptin or its receptor. Antagonists of the Y5 receptor (currently thought to be the NPY 'feeding' receptor) have anti-obesity effects. Melanocortin-4 receptors (MC4-R) are expressed in various hypothalamic regions, including the ventromedial nucleus and ARC. Activation of MC4-R by agonists such as alpha-melanocyte-stimulating hormone (a cleavage product of pro-opiomelanocortin which is expressed in ARC neurones) inhibits feeding and causes weight loss. Conversely, MC4-R antagonists such as 'agouti' protein and agouti gene-related peptide (AGRP) stimulate feeding and cause obesity. Ectopic expression of agouti in the hypothalamus leads to obesity in the AVY mouse, while AGRP is co-expressed by NPY neurones in the ARC. Synthetic MC4-R agonists may ultimately find use as anti-obesity drugs in human subjects Orexins-A and -B, derived from prepro-orexin, are expressed in specific neurones of the lateral hypothalamic area (LHA). Orexin-A injected centrally stimulates eating and prepro-orexin mRNA is up regulated by fasting and hypoglycaemia. The LHA is important in receiving sensory signals from the gut and liver, and in sensing glucose, and orexin neurones may be involved in stimulating feeding in response to falls in plasma glucose.
 ...
PMID:The hypothalamus and the regulation of energy homeostasis: lifting the lid on a black box. 1099 54

The injection of a melanocortin peptide or of melanocortin peptide analogues into the cerebrospinal fluid or into the ventromedial hypothalamus in nanomolar or subnanomolar doses induces a long-lasting inhibition of food intake. The effect keeps significant for up to 9 h and has been observed in all animal species so far tested, the most susceptible being the rabbit. The anorectic effect of these peptides is a primary one, not secondary to the shift towards other components of the complex melanocortin-induced behavioral syndrome, in particular grooming. The site of action is in the brain, and the effect is not adrenal-mediated because it is fully exhibited also by adrenalectomized animals. It is a very strong effect, because the degree of feeding inhibition is not reduced in conditions of hunger, either induced by 24 h starvation, or by insulin-induced hypoglycemia, or by stimulation of gamma-aminobutyric acid (GABA), noradrenergic or opioid systems. The microstructural analysis of feeding behavior suggests that melanocortins act as satiety-inducing agents, because they do not significantly modify the latencies to start eating, but shorten the latencies to stop eating. The mechanism of action involves the activation of melanocortin MC(4) receptors, because selective melanocortin MC(4) receptor antagonists inhibit the anorectic effect of melanocortins, while inducing per se a strong stimulation of food intake and a significant increase in body weight. Melanocortins seem to play an important role in stress-induced anorexia, because such condition, in rats, is significantly attenuated by the blockage of melanocortin MC(4) receptors; such a role is not secondary to an increased release of corticotropin-releasing factor (CRF), because, on the other hand, the CRF-induced anorexia is not affected at all by the blockage of melanocortin MC(4) receptors. The physiological meaning of the feeding inhibitory effect of melanocortins, and, by consequence, the physiological role of melanocortins in the complex machinery responsible for body weight homeostasis, is testified by the hyperphagia/obesity syndromes caused by mutations in the pro-opiomelanocortin (POMC) gene, or in the melanocortin MC(4) receptor gene, or in the agouti locus. Finally, recent evidences suggest that melanocortins could be involved in mediating the effects of leptin, and in controlling the expression of neuropeptide Y (NPY).
 ...
PMID:Role of melanocortins in the central control of feeding. 1103 11

During lactation, hypothalamic levels of neuropeptide Y (NPY) and agouti related protein (AGRP) mRNA are increased, while pro-opiomelanocortin (POMC) mRNA is decreased. Serum leptin levels are also decreased during lactation. These changes may underlie the large increases of both food and water intake that occur in concert with milk production. However, additional hypothalamic substances, such as the novel peptide, orexin, may be involved. In addition, in the presence of chronically suppressed levels of serum leptin, there may be a change in leptin receptor expression in the hypothalamus. The objectives of the present study were to determine if orexin and leptin receptor mRNA levels were changed during lactation. Rats were studied on dioestrus of the oestrous cycle or on day 10 postpartum (the lactating animals were suckling eight pups). Orexin mRNA levels in the lateral hypothalamus did not differ between dioestrus and lactation. There was a significant increase in leptin receptor mRNA levels in the supraoptic nucleus during lactation compared to dioestrus. Furthermore, leptin receptor protein, as determined by immunocytochemistry, was colocalized in virtually all vasopressin and oxytocin cells in the supraoptic nucleus. Lactating animals exhibited a decrease in leptin receptor mRNA in the ventromedial hypothalamic nucleus whereas no change was apparent in other hypothalamic areas compared to the dioestrus animals. These results demonstrate that changes in orexin do not appear to contribute to the increase in food intake during lactation. It is likely that the increases in NPY and ARGP, coupled with the decrease in POMC, are primarily responsible for sustaining the chronic hyperphagia of lactation. The changes observed in leptin receptor expression in the hypothalamus, along with the suppression of serum leptin levels, also suggest that the leptin signalling system may play a significant role in the regulation of food and water intake during lactation.
 ...
PMID:Differential regulation of leptin receptor but not orexin in the hypothalamus of the lactating rat. 1106 23


1 2 3 4 5 6 7 8 9 Next >>