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)

The blood concentration of agouti-related protein (AgRP), a protein related to hyperphagia and obesity, is increased in obese human and fasted lean subjects. Because there is no saturable transport system at the blood-brain barrier for circulating AgRP to reach its central nervous system target, uptake of AgRP by peripheral organs might be physiologically meaningful. Using the biologically active fragment AgRP(82-131), we determined the pharmacokinetics of its radioactively labeled tracer after iv bolus injection and compared it with that of the vascular marker albumin. AgRP enters peripheral organs at different influx rates, all of which were higher than into brain and spinal cord. At 10 min after iv injection, the radioactivity recovered in the liver, which had the fastest influx rate for AgRP, represented intact (125)I-AgRP. The adrenal gland had a moderately fast uptake (but the highest initial volume of distribution), followed by the heart, lungs, and skeletal muscle. By comparison, epididymal fat, testis, and pancreas had low permeability to AgRP. Saturation of influx was determined by coadministration of excess unlabeled AgRP and was shown to be present in the liver and adrenal gland. The influx rate and initial volume of distribution did not show a linear correlation with vascular permeability or regional blood flow. AgRP uptake by the liver and epididymal fat was significantly increased by overnight fasting, whereas that by the adrenal gland was significantly decreased in fasted mice. Thus, the differential uptake of AgRP by peripheral organs could be a regulated process that is modulated by food deprivation.
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PMID:Selective tissue uptake of agouti-related protein(82-131) and its modulation by fasting. 1614 94

Normal aging in humans and rodents is accompanied by a progressive increase in adiposity. To investigate the role of hypothalamic neuronal circuits in this process, we used a Cre-lox strategy to create mice with specific and progressive degeneration of hypothalamic neurons that express agouti-related protein (Agrp) or proopiomelanocortin (Pomc), neuropeptides that promote positive or negative energy balance, respectively, through their opposing effects on melanocortin receptor signaling. In previous studies, Pomc mutant mice became obese, but Agrp mutant mice were surprisingly normal, suggesting potential compensation by neuronal circuits or genetic redundancy. Here we find that Pomc-ablation mice develop obesity similar to that described for Pomc knockout mice, but also exhibit defects in compensatory hyperphagia similar to what occurs during normal aging. Agrp-ablation female mice exhibit reduced adiposity with normal compensatory hyperphagia, while animals ablated for both Pomc and Agrp neurons exhibit an additive interaction phenotype. These findings provide new insight into the roles of hypothalamic neurons in energy balance regulation, and provide a model for understanding defects in human energy balance associated with neurodegeneration and aging.
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PMID:Effects of hypothalamic neurodegeneration on energy balance. 1629 93

Obesity is a major global epidemic, with over 300 million obese people worldwide, and nearly 1 billion overweight adults. Being overweight carries significant health risks, reduced quality of life, and impaired socioeconomic success, with profound consequences for health expenditure. The most successful treatment for obesity is gastric bypass surgery, which acts in part by reducing appetite through alterations in gut hormones. Circulating gut hormones, secreted or suppressed after eating food, act in the brain, particularly the hypothalamus, to alter hunger and fullness. Stomach-derived ghrelin increases food intake even in those with anorexia from chronic illness, while pancreatic polypeptide (PP), intestinal peptide YY 3-36 (PYY), oxyntomodulin, and other hormones reduce food intake and appetite. While obese subjects have appropriate reductions in orexigenic ghrelin, other gut-hormone disturbances may contribute to obesity such as reduced anorexigenic PYY and PP. Prader-Willi syndrome (PWS) arises from the loss of paternally inherited genes on chromosome 15q11-13, leading to life-threatening insatiable hunger and obesity from early childhood, through developmental brain, particularly hypothalamic defects. The study of genetically homogenous causes of abnormal-feeding behavior helps our understanding of appetite regulation. PWS subjects have inappropriately elevated plasma ghrelin for their obesity, at least partly explained by preserved insulin sensitivity. It remains unproven if their hyperghrelinemia or other gut-hormone abnormalities contribute to the hyperphagia in PWS, in addition to brain defects. Postmortem human hypothalamic studies and generation of animal models of PWS can also provide insight into the pathophysiology of abnormal-feeding behavior. Changes in orexigenic NPY and AGRP hypothalamic neurons, or anorexigenic oxytocin neurons have been found in illness and PWS. Functional neuroimaging studies, using PET and fMRI, will also allow us to tease apart the hormonal and brain pathways responsible for controlling human appetite, and their defects in obesity.
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PMID:The hypothalamus, hormones, and hunger: alterations in human obesity and illness. 1687 68

Elevated anxiety symptoms have been reported to be present in many patients with diabetes mellitus. The underlying mechanisms by which diabetes mellitus influences behavior remain to be determined. We assessed feeding and anxiety behaviors in spontaneously diabetic Ins2Akita mice. We measured blood glucose, body weight, and food and water intakes in C57BL/6 heterozygote Ins2Akita mice. The behavioral properties of Ins2Akita mice were assessed in an open-field test and an elevated plus-maze. The gene expression of hypothalamic neuropeptides was examined in non-food-deprived Ins2Akita mice. Body weights of the Ins2Akita mice were less than those of the age-matched C57BL/6 mice, as controls. Food and water intakes were increased in the Ins2Akita mice. In the open-field test, the Ins2Akita mice had decreased locomotor activity and increased immobilization time. The Ins2Akita mice exhibited anxiety behavior in the elevated plus-maze. RT-PCR analysis showed decreased proopiomelanocortin (POMC) mRNA expression and increased agouti-related protein (AGRP) mRNA expression in Ins2Akita mice. There were no significant differences in hypothalamic ghrelin mRNA expression. These observations indicate that Ins2Akita mice, which are characterized by hypoinsulinemia and hyperglycemia, exhibited hyperphagia and anxiety behavior; the mechanism of action involved the activation of hypothalamic AGRP and the inactivation of hypothalamic POMC. In addition, Ins2Akita mice are a useful model for understanding the mechanisms involved in the psychological complications of diabetes mellitus. Further, melanocortin systems may be therapeutic targets not only for diabetes but also for its associated complications.
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PMID:Ins2Akita mice exhibit hyperphagia and anxiety behavior via the melanocortin system. 1733 40

The ability of acute exercise to stimulate appetite and food intake depends on intensity, duration, and agouti-related protein (AGRP) levels. Fasting, as well as any negative energy balance, has been reported to increase AGRP expression in the arcuate nucleus (ARC) of the hypothalamus and other extra-hypothalamic tissues in human and rats. The purpose of the present study was to investigate the response of plasma AGRP, GH and insulin to a single circuit-resistance exercise. Twenty volunteer male college students completed a single bout of circuit-resistance training (10 exercises at 35% of 1RM). Blood samples were collected before, immediately and 30 min following the exercise protocol. Plasma AGRP and GH levels showed a significant increase immediately after exercise and returned to pre exercise values during the recovery period. The data indicate that exercise protocol was able to increase plasma AGRP and GH levels. A higher plasma AGRP level might result in an acute exercise-induced hyperphagia and help to fuel post-exercise restoration processes.
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PMID:Plasma agouti-related protein (AGRP), growth hormone, insulin responses to a single circuit-resistance exercise in male college students. 1736 50

Food intake and activity-induced thermogenesis are important components of energy balance regulation. The molecular mechanism underlying the coordination of food intake with locomotory behavior to maintain energy homeostasis is unclear. We report that the brain-specific homeobox transcription factor Bsx is required for locomotory behavior, hyperphagia, and expression of the hypothalamic neuropeptides Npy and Agrp, which regulate feeding behavior and body weight. Mice lacking Bsx exhibit reduced locomotor activity and lower expression of Npy and Agrp. They also exhibit attenuated physiological responses to fasting, including reduced increase of Npy/Agrp expression, lack of food-seeking behavior, and reduced rebound hyperphagia. Furthermore, Bsx gene disruption rescues the obese phenotype of leptin-deficient ob/ob mice by reducing their hyperphagia without increasing their locomotor activity. Thus, Bsx represents an essential factor for NPY/AgRP neuronal function and locomotory behavior in the control of energy balance.
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PMID:A role for brain-specific homeobox factor Bsx in the control of hyperphagia and locomotory behavior. 1755 Jul 80

The melanocortin family of receptors (MC 1-5R) and their endogenous peptide ligands (alpha, beta, gamma- MSH and ACTH) have been implicated in the control of a wide variety of behavioral and physiological functions including the homeostatic control of food intake and body weight. In rodent models, melanocortin agonists including the nonselective peptide MTII have been shown to decrease food intake and body weight while antagonists such as SHU9119 and AGRP have been shown to stimulate food intake and increase body weight. Deletion of either the MC3R or MC4R in mice was found to be associated with obesity although hyperphagia was only observed in the MC4R deficient mice. Similarly in humans, inactivating mutations of the MC4R have been found in as many as six percent of obese individuals. The suggestion from these findings that activation of MC4Rs would have an anorectic effect in humans has resulted in efforts to produce selective agonists for the treatment of obesity. Over the past decade, efforts to develop MC4R selective small molecule and peptide agonists have been met with fractional success. Many small molecule agonists have been identified; however, few have been shown to have activity in vivo. While their use as therapeutics may have limitations, selective and potent peptide agonists have been shown by several investigators to decrease food intake and body weight in rodent models. The subject of the current review is to examine the progress made to date on producing both small molecule and peptide MC4R agonists as potential therapeutics for obesity.
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PMID:Melanocortin-4 receptor agonists for the treatment of obesity. 1758 32

Dmbx1 is a paired-class homeodomain transcription factor. We show here that mice deficient in Dmbx1 exhibit severe leanness associated with hypophagia and hyperactivity and that isolation of a Dmbx1(-/-) mouse from its cohabitants induces self-starvation, sometimes leading to death, features similar to those of anorexia nervosa in humans. Interestingly, overexpression of agouti in Dmbx1(-/-) mice failed to induce aspects of the A(y)/a phenotype, including hyperphagia, obesity, and diabetes mellitus. In Dmbx1(-/-) mice, administration of agouti-related protein increased cumulative food intake for the initial 6 h but significantly decreased it over 24- and 48-h periods. In addition, Dmbx1 was shown to be expressed at embryonic day 15.5 in the lateral parabrachial nucleus, the rostral nucleus of the tractus solitarius, the dorsal motor nucleus of the vagus, and the reticular nucleus in the brainstem, all of which receive melanocortin signaling, indicating involvement of Dmbx1 in the development of the neural network for the signaling. Thus, Dmbx1 is essential for various actions of agouti-related protein and plays a role in normal regulation of energy homeostasis and behavior.
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PMID:Dmbx1 is essential in agouti-related protein action. 1787 59

Hypothalamic neurons that express agouti-related protein (AgRP) and neuropeptide Y (NPY) are thought to be important for regulation of feeding, especially under conditions of negative energy balance. The expression of NPY and AgRP increases during lactation and may promote the hyperphagia that ensues. We explored the role of AgRP neurons in reproduction and lactation, using a mouse model in which AgRP-expressing neurons were selectively ablated by the action of diphtheria toxin. We show that ablation of AgRP neurons in neonatal mice does not interfere with pregnancy, parturition, or lactation, suggesting that early ablation allows compensatory mechanisms to become established. However, ablation of AgRP neurons after lactation commences results in rapid starvation, indicating that both basal feeding and lactation-induced hyperphagia become dependent on AgRP neurons in adulthood. We also show that constitutive inactivation of Npy and Agrp genes does not prevent pregnancy or lactation, nor does it protect lactating dams from diphtheria toxin-induced starvation.
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PMID:Role of agouti-related protein-expressing neurons in lactation. 1797 21

Human genetic data indicate impaired synthesis or processing of POMC results in obesity. We have used a mouse model of POMC deficiency (Pomc null) to explore the role of POMC-derived peptides in energy homeostasis. The phenotype of Pomc null mice recapitulates the clinical syndrome seen in humans congenitally lacking POMC. Loss of only one copy of the Pomc gene is sufficient to render mice susceptible to the effects of high fat feeding, emphasizing an important gene-environment interaction predisposing to obesity. Our studies indicate that POMC-derived peptides have influences on the response to a high fat diet, including a major influence on the dietary preference for fat. Pomc null mice are unusual in that obesity and hyperphagia develop in the absence of circulating glucocorticoid (GC). To investigate the interaction between GCs and the melanocortin system, we administered corticosterone to Pomc null mice. They appear hypersensitive to the adverse metabolic effects of GCs, developing hypertension, an exacerbation of both hyperphagia and obesity and a profound insulin resistance. GC treatment of Pomc null mice significantly increases the expression of the melanocortin antagonist agouti-related protein (AgRP). On-going studies in mice lacking both AgRP and Pomc will determine whether the metabolic phenotype seen with this GC therapy is due to a lack of melanocortin peptide, the unopposed action of AgRP or a combination of both.
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PMID:Pro-opiomelanocortin (POMC)-derived peptides and the regulation of energy homeostasis. 1884 May 2


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