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)

Various aspects of the complex spatio-temporal patterning of hypothalamic signaling that leads to the development of synchronized nocturnal feeding in the rat are critically examined. Undoubtedly, as depicted in Fig. 7, a distinct ARN in the hypothalamus is involved in the control of nocturnal appetite. At least four basic elements operate within this ARN. These are: 1) A discrete appetite-driving or orexigenic network of NPY, NE, GABA, GAL, EOP, and orexin transduces and releases appetite-stimulating signals. 2) Similarly, anorexigenic signal-producing pathways (e.g., CRH, GLP-1, alpha MSH, and CART) orchestrate neural events for dissipation of appetite and to terminate feeding, possibly by interrupting NPY efflux and action at a postsynaptic level within the hypothalamus. It is possible that some of these may represent the physiologically relevant "off" switches under the influence of GABA alone, or AgrP alone, or in combination with NPY released from the NPY-, GABA-, and AgrP-coproducing neurons. 3) Recent evidence shows that neural elements in the VMN-DMN complex tonically restrain the orexigenic signals during the intermeal interval; the restraint is greatly aided by leptin's action via diminution of orexigenic (NPY) and augmentation of anorexigenic (GLP-1, alpha MSH, and CART) signals. Since interruption of neurotransmission in the VMN resulted in hyperphagia and development of leptin resistance, it seems likely that the VMN is an effector site for the restraint exercised by leptin. The daily rhythms in leptin synthesis and release are temporally dissociable because the onset of daily rise in leptin gene expression in adipocytes precedes that in leptin secretion. Nevertheless, these rhythms are in phase with daily ingestive behavior because the peak in circulating leptin levels occurs during the middle of the feeding period. These observations, coupled with the fact that circulating levels of leptin are directly related to adiposity, pose a new challenge for elucidating the precise role of leptin in daily patterning of feeding in the rat. 4) A neural timing mechanism also operates upstream from the ARN in the daily management of energy homeostasis. Although the precise anatomical boundaries are not clearly defined, this device is likely to be composed of a group of neurons that integrate incoming internal and external information for the timely onset of the drive to eat. Evidently, this network operates independently in primates, but it is entrained to the circadian time keeper in the SCN of rodents. Apart from its role in the onset of drive to eat, the circadian patterns of gene expression of NPY, GAL, and POMC denote independent control of the timing device on the synthesis and availability for release of orexigenic signals. The VMN-DMN-PVN complex is apparently an integrated constituent of the timing mechanism in this context, because lesions in each of these sites result in loss of regulated feeding. The accumulated evidence points to the PVN and surrounding neural sites within this framework as the primary sites of release and action of various orexigenic and anorexigenic signals. A novel finding is the identification of the interconnected wiring of the DMN-mPVN axis that may mediate leptin restraint on NPY-induced feeding. The chemical phenotypes of leptin and NPY target neurons in this axis remain to be identified. These multiple orexigenic and anorexigenic pathways in the hypothalamic ARN appear to represent redundancy, a characteristic of regulated biological systems to provide a "fail-safe" neural mechanism to meet an organism's constant energy needs for growth and maintenance. Within this formulation, the coexisting orexigenic signals (NPY, NE, GAL, GABA, and AgrP) represent either another level of redundancy or it is possible that these signals operate within the ARN as reinforcing agents to varying degrees under different circumstances. (ABSTRACT TRUNCATED)
 ...
PMID:Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. 1004 74

Intraaccumbens infusions of the GABA(B) agonist baclofen are known to stimulate food intake in the rat. The aim of the present study was to evaluate the effects of baclofen infusion on nonfood-related chewing and on the consumption of a palatable fluid. Rats were bilaterally infused with baclofen (188 ng in 1 microL) or saline, and tested in a situation in which food was available in one or two locations and wood blocks might also be present. Baclofen-infused animals showed no enhancement of chewing directed at the wood blocks, but showed increased food consumption regardless of food location. In a second, separate test we recorded the microstructural parameters for drinking of a palatable glucose/saccharin mixture. Baclofen infusion had no effect on overall intake, although bout size was reduced and the number of bouts was increased. These data confirm that baclofen-stimulated food intake following accumbens infusion is a robust and substantial phenomenon that appears to be selective to solid food. It is likely to result from relatively direct activation of neural circuits for feeding, rather than an indirect facilitation consequent upon changes in taste processings, as has been suggested for some other examples of drug-induced hyperphagia.
 ...
PMID:Intraaccumbens baclofen selectively enhances feeding behavior in the rat. 1071 85

Benzodiazepine receptor (BDZR) ligands are structurally diverse compounds that bind to specific binding sites on GABA(A) receptors and allosterically modulate the effect of GABA on chloride ion flux. The binding of BDZR ligands to this receptor system results in activity at multiple behavioral endpoints, including anxiolytic, sedative, anticonvulsant, and hyperphagic effects. In the work presented here, a computational procedure developed in our laboratory has been used to obtain a 3D pharmacophore for ligand recognition of the GABA(A)/BDZRs initiating the hyperphagic response. To accomplish this goal, 17 structurally diverse compounds, previously assessed in our laboratory for activity at the hyperphagic endpoint, were used. The result is a four-component 3D pharmacophore. It consists of two proton acceptor atoms, the centroid of an aromatic ring and the centroid of a hydrophobic moiety in a common geometric arrangement in all compounds with activity at this endpoint. This 3D pharmacophore was then assessed and successfully validated using three different tests. First, two BDZR ligands, which were included as negative controls in the set of seventeen compounds used for the pharmacophore development, did not fit the pharmacophore. Second, some benzodiazepine ligands known to have activity at the hyperphagia endpoint, but not included in the pharmacophore development, were used as positive controls and were found to fit the pharmacophore. Finally, using the 3D pharmacophore developed in the present work to search 3D databases, over 50 classical benzodiazepines were found. Among them, were benzodiazepine ligands known to have an effect at the hyperphagic endpoint. In addition, the novel compounds also found in this search are promising therapeutic agents that could beneficially affect feeding behavior.
 ...
PMID:Benzodiazepine-induced hyperphagia: development and assessment of a 3D pharmacophore by computational methods. 1079 22

The administration of leptin to leptin-deficient humans, and the analogous Lepob/Lepob mice, effectively reduces hyperphagia and obesity. But common obesity is associated with elevated leptin, which suggests that obese humans are resistant to this adipocyte hormone. In addition to regulating long-term energy balance, leptin also rapidly affects neuronal activity. Proopiomelanocortin (POMC) and neuropeptide-Y types of neurons in the arcuate nucleus of the hypothalamus are both principal sites of leptin receptor expression and the source of potent neuropeptide modulators, melanocortins and neuropeptide Y, which exert opposing effects on feeding and metabolism. These neurons are therefore ideal for characterizing leptin action and the mechanism of leptin resistance; however, their diffuse distribution makes them difficult to study. Here we report electrophysiological recordings on POMC neurons, which we identified by targeted expression of green fluorescent protein in transgenic mice. Leptin increases the frequency of action potentials in the anorexigenic POMC neurons by two mechanisms: depolarization through a nonspecific cation channel; and reduced inhibition by local orexigenic neuropeptide-Y/GABA (gamma-aminobutyric acid) neurons. Furthermore, we show that melanocortin peptides have an autoinhibitory effect on this circuit. On the basis of our results, we propose an integrated model of leptin action and neuronal architecture in the arcuate nucleus of the hypothalamus.
 ...
PMID:Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. 1137 81

This study was designed to compare the effects of muscimol (GABA(A) agonist), baclofen (GABA(B) agonist) and nipecotic acid (GABA uptake inhibitor) on food intake in two chicken strains (meat-type and layer-type chicks). The intracerebroventricular (ICV) injection of all GABA agents induced hyperphagia in layer-type chicks. However, in broiler chicks, there were similar tendencies with muscimol and nipecotic acid but not significantly different. Conversely, ICV injection of baclofen depressed feeding of broiler chicks. These results suggest that there are some differences in central GABAergic systems between these strains of chicks, but GABAergic systems have an important role in the regulation of food intake in neonatal chicks.
 ...
PMID:Intracerebroventricular injection of muscimol, baclofen or nipecotic acid stimulates food intake in layer-type, but not meat-type, chicks. 1464 53

Neuropeptide Y is the most potent physiological appetite transducer known. The NPY network is the conductor of the hypothalamic appetite regulating orchestra in the arcuate nucleus-paraventricular nucleus (ARC-PVN) of the hypothalamus. NPY and cohorts, AgrP, GABA and adrenergic transmitters, initiate appetitive drive directly through Y1, Y5, GABAA and alpha1 receptors, co-expressed in the magnocellular PVN (mPVN) and ARC neurons and by simultaneously repressing anorexigenic melanocortin signaling in the ARC-PVN axis. The circadian and ultradian rhythmicities in NPY secretion imprint the daily circadian and episodic feeding patterns. Although a number of afferent hormonal signals from the periphery can directly modulate NPYergic signaling, the reciprocal circadian and ultradian rhythmicities of anorexigenic leptin from adipocytes and orexigenic ghrelin from stomach, encode a corresponding pattern of NPY discharge for daily meal patterning. Subtle and progressive derangements produced by environmental and genetic factors in this exquisitely intricate temporal relationship between the two opposing humoral signals and the NPY network promote hyperphagia and abnormal rate of weight gain culminating in obesity and attendant metabolic disorders. Newer insights at cellular and molecular levels demonstrate that a breakdown of the integrated circuit due both to high and low abundance of NPY at target sites, underlies hyperphagia and increased adiposity. Consequently, interruption of NPYergic signaling at a single locus with NPY receptor antagonists may not be the most efficacious therapy to suppress hyperphagia and obesity. Central leptin gene therapy in rodents has been shown to subjugate, i.e. bring under homeostatic control, NPYergic signaling and suppress the age-related and dietary obesity for extended periods and thus shows promise as a newer treatment modality to curb the pandemic of obesity and metabolic syndrome.
 ...
PMID:NPY and cohorts in regulating appetite, obesity and metabolic syndrome: beneficial effects of gene therapy. 1533 72

This paper updates an early review on benzodiazepine-enhanced food intake, published in the first issue of Appetite, and describes the considerable advances since then in the pharmacology of benzodiazepines, their sites and mechanisms of action, and in understanding the psychological processes leading to the increase in food consumption. A great diversity of benzodiazepine receptor ligands have been developed, many of which affect food intake. Agonists can be divided into full agonists (which produce the full spectrum of benzodiazepine effects) and partial agonists (which are more selective in their effects). In addition, inverse agonists have been identified, with high affinity for benzodiazepine receptors but having negative efficacy: these drugs exhibit anorectic properties. Benzodiazepine receptors are part of GABA(A) receptor complexes, and ligands thereby modulate inhibitory neurotransmission in the brain. Molecular approaches have identified a palette of receptor subunits from which GABA(A) receptors are assembled. In all likelihood, benzodiazepine-induced hyperphagia is mediated by the alpha2/alpha3 subtype not the alpha1 subtype. Novel alpha2/alpha3 selective compounds will test this hypothesis. A probable site of action in the caudal brainstem for benzodiazepines is the parabrachial nucleus. Behavioural evidence strongly indicates that a primary action of benzodiazepines is to enhance the positive hedonic evaluation (palatability) of tastes and foodstuffs. This generates the increased food intake and instrumental responding for food rewards. Therapeutic applications may derive from the actions of benzodiazepine agonists and inverse agonists on food procurement and ingestion.
 ...
PMID:Palatability-dependent appetite and benzodiazepines: new directions from the pharmacology of GABA(A) receptor subtypes. 1580 88

Although the role of orexins in sleep/wake cycle and feeding behavior is well established, underlying mechanisms have not been fully understood. An attempt has been made to investigate the role of GABA(A) receptors and their benzodiazepine site on the orexin-A induced response to feeding. Different groups of rats were food deprived overnight and next day injected intracerebroventricularly (icv) with vehicle (artificial CSF; 5 microl/rat) or orexin-A (20-50 nM/rat) and the animals were given free access to food. Cumulative food intake was measured during light phase of light/dark cycle at 1-, 2-, 4- and 6-h post-injection time points. Orexin-A (30-50 nM/rat, icv) stimulated food intake at all the time points (P < 0.05). Prior administration of GABA(A) receptor agonists muscimol (25 ng/rat, icv) and diazepam (0.5 mg/kg, ip) at subeffective doses significantly potentiated the hyperphagic effect of orexin-A (30 nM/rat, icv). However, the effect was negated by the GABA(A) receptor antagonist bicuculline (1 mg/kg, ip). Interestingly, benzodiazepine receptor antagonist flumazenil (5 ng/rat, icv), augmented the orexin-A (30 nM/rat, icv) induced hyperphagia; the effect may be attributed to the intrinsic activity of the agent. The results suggest that the hyperphagic effect of orexin-A, at least in part, is mediated by enhanced GABA(A) receptor activity.
 ...
PMID:GABA(A) receptors mediate orexin-A induced stimulation of food intake. 1616 44

Work over the past decade has supported the idea that discrete aspects of appetitive motivation are differentially mediated by separate but interacting neurochemical systems within the nucleus accumbens (Acb). We review herein a series of studies in rats comparing the effects of manipulating Acb amino acid, opioid, acetylcholine, and dopamine systems on tests of free-feeding and food-reinforced operant responding. Results from our laboratory and in the literature support three general conclusions: (1) GABA output neurons localized exclusively within the Acb shell directly influence hypothalamic effector mechanisms for feeding motor patterns, but do not participate in the execution of more complex food-seeking strategies; (2) enkephalinergic neurons distributed throughout the Acb and caudate-putamen mediate the hedonic impact of palatable (high sugar/fat) foods, and these neurons are under modulatory control by striatal cholinergic interneurons; and (3) dopamine transmission in the Acb governs general motoric and arousal processes related to response selection and invigoration, as well as motor learning-related plasticity. These dissociations may reflect the manner in which these neurochemical systems differentially access pallido-thalamo-cortical loops reaching the voluntary motor system (in the case of opioids and dopamine), versus more restricted efferent connections to hypothalamic motor/autonomic control columns (in the case of Acb shell GABA and glutamate systems). Moreover, we hypothesize that while these systems work in tandem to coordinate the anticipatory and consummatory phases of feeding with hypothalamic energy-sensing substrates, the striatal opioid network evolved a specialized capacity to promote overeating of energy-dense foods beyond acute homeostatic needs, to ensure an energy reserve for potential future famine.
 ...
PMID:Corticostriatal-hypothalamic circuitry and food motivation: integration of energy, action and reward. 1628 9

To investigate the role of corticolimbic input in modulating feeding-related nucleus accumbens (Acb) circuitry, researchers temporarily deactivated sites within the basolateral amygdaloid complex (BLA) or central amygdaloid region (CeA) via GABA(A) agonist (muscimol) infusions and measured feeding responses following muscimol infusions into the Acb shell. Hyperphagia elicited by intra-Acb shell muscimol was not altered by coinfusions of intra-BLA muscimol. In contrast, muscimol infusions into the CeA dose-dependently reduced feeding elicited either by intra-Acb shell GABA(A) receptor stimulation or by food deprivation and produced a syndrome of forepaw treading. Intra-CeA tetrodotoxin infusions also blocked intra-Acb shell muscimol-induced hyperphagia. Hence, feeding elicited by intra-Acb shell GABA(A) receptor stimulation requires intact neural output from the CeA but not the BLA.
 ...
PMID:Hyperphagia induced by GABAA receptor-mediated inhibition of the nucleus accumbens shell: dependence on intact neural output from the central amygdaloid region. 1630 Apr 26


<< Previous 1 2 3 4 Next >>