Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report two cases of children with disabling daytime sleepiness associated with suprasellar tumors and hypothalamic obesity. Multiple sleep latency testing demonstrated features consistent with severe narcolepsy, with sleep latencies of 0.25 and 0.75 minutes, and REM latencies of 2.1 and 1.5 minutes, respectively. An additional patient with hypothalamic damage secondary to a brain tumor, who was thought to be in a vegetative state, had features of narcolepsy on polysomnography. All children responded well to treatment with stimulants. We speculate that secondary narcolepsy associated with hypothalamic tumors is due to damage or loss of hypothalamic hypocretin-containing neurons. In view of the good response to treatment, we recommend that all children with excessive daytime sleepiness and hypothalamic damage be evaluated for narcolepsy.
 ...
PMID:Secondary narcolepsy in children with brain tumors. 1268 85

Specialized neurons utilize glucose as a signaling molecule to alter their firing rate. Glucose-excited (GE) neurons increase and glucose-inhibited (GI) neurons reduce activity as ambient glucose levels rise. Glucose-induced changes in the ATP-to-ADP ratio in GE neurons modulate the activity of the ATP-sensitive K(+) channel, which determines the rate of cell firing. The GI glucosensing mechanism is unknown. We postulated that glucokinase (GK), a high-Michaelis constant (K(m)) hexokinase expressed in brain areas containing populations of GE and GI neurons, is the controlling step in glucosensing. Double-label in situ hybridization demonstrated neuron-specific GK mRNA expression in locus ceruleus norepinephrine and in hypothalamic neuropeptide Y, pro-opiomelanocortin, and gamma-aminobutyric acid neurons, but it did not demonstrate this expression in orexin neurons. GK mRNA was also found in the area postrema/nucleus tractus solitarius region by RT-PCR. Intracarotid glucose infusions stimulated c-fos expression in the same areas that expressed GK. At 2.5 mmol/l glucose, fura-2 Ca(2+) imaging of dissociated ventromedial hypothalamic nucleus neurons demonstrated GE neurons whose intracellular Ca(2+) oscillations were inhibited and GI neurons whose Ca(2+) oscillations were stimulated by four selective GK inhibitors. Finally, GK expression was increased in rats with impaired central glucosensing (posthypoglycemia and diet-induced obesity) but was unaffected by a 48-h fast. These data suggest a critical role for GK as a regulator of glucosensing in both GE and GI neurons in the brain.
 ...
PMID:Glucokinase is the likely mediator of glucosensing in both glucose-excited and glucose-inhibited central neurons. 1208 33

A wide spectrum of diseases, as well as states of attenuated ability to heal and recover, can be traced to over- or underweight. Patients at the extremes of the energy balance spectrum are becoming more and more common. In order to provide adequate care for such patients an understanding of the mechanisms governing feeding behaviour is required. In the last decade, important advances have been made in this direction, as several factors mediating signals of hunger and satiety to and within the brain have been identified. These factors include hormonal signals (such as leptin and insulin) from the energy stores as well as neuronal influences (via the vagus nerve) from the digestive tract. The information encoded therein is routed to specific nuclei of the hypothalamus and brain stem, respectively, leading to activation of complex neuronal networks spanning the most rostral regions of the brain all the way to the effector neurones of the autonomic nervous system located in the spinal cord. Several recently characterized neuropeptides showing potent stimulation of appetite (neuropeptide Y, agouti gene-related peptide, orexin, melanin-concentrating hormone) and satiety (melanocortins, cholecystokinin, cocaine- and amphetamine-regulated transcript) have been localized to these pathways. These peptides, and the mechanisms through which they operate, offer promise for new therapeutic strategies in the treatment of obesity and anorexia.
 ...
PMID:[Peptides are opening the door for novel treatments of obesity and loss of appetite]. 1252 88

The hypocretins (1 and 2) have emerged as key regulators of sleep and wakefulness. We developed a high-throughput enzyme immunoassay (EIA) to measure total brain hypocretin levels from large numbers of mice. Hypocretin levels were not altered by circadian time or age. However, significant differences in one or both hypocretin peptides were observed between different mouse strains. We studied hypocretin levels in knockout and transgenic mouse models with obesity, circadian gene mutations or monoaminergic defects. Compared to controls, only histamine receptor knockouts had lower hypocretin levels. This was most pronounced in H1 receptor knockouts suggesting the existence of a positive feedback loop between hypocretin and histaminergic neurons.
 ...
PMID:Measurement of hypocretin/orexin content in the mouse brain using an enzyme immunoassay: the effect of circadian time, age and genetic background. 1253

Previous reports implicate the orexins in eating and body weight regulation. This study investigated possible functional relationships between hypothalamic orexins and circulating hormones or metabolites. In situ hybridization and quantitative PCR were used to examine orexin expression in the perifornical hypothalamus (PF) of rats and mice on diets varying in fat content and with differential propensity toward obesity. The results showed that orexin gene expression was stimulated by a high-fat diet in close association with elevated triglyceride levels, suggesting a functional relationship between these measures. Results obtained in obesity-prone rats and mice revealed a similar increase in orexin in close relation to triglycerides. A direct test of this orexin-triglyceride link was performed with Intralipid, which increased PF orexin expression along with circulating triglycerides. Whereas PF galanin is similarly stimulated by dietary fat, double-labeling immunofluorescence studies showed that orexin and galanin neurons are anatomically distinct. This evidence suggests that the orexins, like galanin, are "fat-responsive" peptides that respond to circulating lipids.
 ...
PMID:Peptides that regulate food intake: orexin gene expression is increased during states of hypertriglyceridemia. 1256 Feb 2

Obesity is an epidemic that has plagued industrialized nations for decades. However, before effective treatments can be implemented, the pathways and transmitters involved in appetite and food-seeking behavior must first be resolved. Food-seeking behavior involves the integration of three separate systems: appetite, wakefulness and an increase in sympathetic activity. The recent discovery of two hypothalamic peptides, orexin A/hypocretin 1 and orexin B/hypocretin 2, found exclusively in the lateral hypothalamus, may lead to a better understanding of how the integration of these three systems involved in appetite are modulated through a common neurotransmitter. Two known receptors, OX(1)R and OX(2)R, have been reported and are expressed throughout the entire neuraxis. The physiological role of orexin/hypocretin relative to food intake, sleep-wake cycling and autonomic activity has emerged in both animals and humans. The increased understanding of the orexin system has directed attention to the development of novel chemicals acting on orexin receptors as potential targets for obesity, narcolepsy and cardiovascular disease. (c) 2002 Prous Science. All rights reserved.
 ...
PMID:Orexin/Hypocretin System: Obesity, Narcolepsy and Beyond. 1267 59

Corticolimbic circuits involving the prefrontal cortex, amygdala, and ventral striatum determine the reward value of food and might play a role in environmentally induced obesity. Chemical manipulation of the nucleus accumbens shell (AcbSh) has been shown to elicit robust feeding and Fos expression in the hypothalamus and other brain areas of satiated rats. To determine the neurochemical phenotype of hypothalamic neurons receiving input from the AcbSh, we carried out c-Fos/peptide double-labeling immunohistochemistry in various hypothalamic areas known to contain feeding peptides, from rats that exhibited a significant feeding response after AcbSh microinjection of the GABA(A) agonist muscimol. In the perifornical area, a significantly higher percentage of orexin neurons expressed Fos after muscimol compared with saline injection. In contrast, Fos expression was not induced in melanin-concentrating hormone and cocaine-amphetamine-related transcript (CART) neurons. In the arcuate nucleus, Fos activation was significantly lower in neurons coexpressing CART and proopiomelanocortin, and there was a tendency for higher Fos expression in neuropeptide Y neurons. In the paraventricular nucleus, no significant activation of oxytocin and CART neurons was found. Thus AcbSh manipulation may elicit food intake through coordinated stimulation of hypothalamic neurons expressing orexigenic peptides and suppression of neurons expressing anorexigenic peptides. However, activation of many neurons not expressing these peptides suggests that additional peptides/transmitters in the lateral hypothalamus and accumbens projections to other brain areas might also be involved.
 ...
PMID:Peptides that regulate food intake: appetite-inducing accumbens manipulation activates hypothalamic orexin neurons and inhibits POMC neurons. 1273 70

The neuropeptides orexins/hypocretins are essential for normal wakefulness and energy balance, and disruption of their function causes narcolepsy and obesity. Although much is known of the role of orexins in sleep/wake behavior, it remains unclear how they stimulate feeding and metabolism. One of the main targets of orexinergic neurons is the arcuate nucleus (ARC) of the hypothalamus, which plays a key role in feeding and energy homeostasis. By combining patch-clamp and RT-multiplex PCR analysis of individual neurons in mouse brain slices, we show that an electrophysiologically distinct subset of ARC neurons coexpress orexin receptors and glutamate decarboxylase-67 and are excited by orexin. Acting on postsynaptic orexin type 2 receptors, orexin activates a sodium-calcium exchange current, thereby depolarizing the cell and increasing its firing frequency. Because GABA is a potent stimulus for feeding, in both the ARC and its main projection site, these results suggest a mechanism for how orexin may control appetite.
 ...
PMID:Orexin excites GABAergic neurons of the arcuate nucleus by activating the sodium--calcium exchanger. 1283 17

Leptin, the long-sought satiety factor of adipocytes origin, has emerged as one of the major signals that relay the status of fat stores to the hypothalamus and plays a significant role in energy homeostasis. Understanding the mechanisms of leptin signaling in the hypothalamus during normal and pathological conditions, such as obesity, has been the subject of intensive research during the last decade. It is now established that leptin action in the hypothalamus in regulation of food intake and body weight is mediated by a neural circuitry comprising of orexigenic and anorectic signals, including NPY, MCH, galanin, orexin, GALP, alpha-MSH, NT, and CRH. In addition to the conventional JAK2-STAT3 pathway, it has become evident that PI3K-PDE3B-cAMP pathway plays a critical role in leptin signaling in the hypothalamus. It is now established that central leptin resistance contributes to the development of diet-induced obesity and ageing associated obesity. Central leptin resistance also occurs due to hyperleptinimia produced by exogenous leptin infusion. A defective nutritional regulation of leptin receptor gene expression and reduced STAT3 signaling may be involved in the development of leptin resistance in DIO. However, leptin resistance in the hypothalamic neurons may occur despite an intact JAK2-STAT3 pathway of leptin signaling. Thus, in addition to defective JAK2-STAT3 pathway, defects in other leptin signaling pathways may be involved in leptin resistance. We hypothesize that defective regulation of PI3K-PDE3B-cAMP pathway may be one of the mechanisms behind the development of central leptin resistance seen in obesity.
 ...
PMID:Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance. 1472 56

Removal of glucocorticoids by adrenalectomy (ADX) reduces food intake and body weight in rodents and prevents excessive weight gain in many genetic and dietary models of obesity. Glucocorticoids play a key role to promote positive energy balance in normal and pathological conditions, at least in part, by altering the sensitivity to hypothalamic peptides. The hyperphagia after central neuropeptide Y administration, for example, is attenuated by ADX, and there is evidence that glucocorticoids influence both MCH and orexin A activity. In the present study, feeding responses to third ventricular MCH and orexin A were measured in rats after bilateral ADX or sham surgery. ADX rats were significantly less sensitive to the orexigenic action of third ventricular MCH, whereas orexin A-induced hyperphagia was unaffected. Replacement of corticosterone in the drinking water of ADX rats reversed the effects of ADX on MCH sensitivity. Although we found significant populations of glucocorticoid receptors in the lateral hypothalamus, none were colocalized with either MCH or orexin A-containing cell bodies. Furthermore, whereas ADX significantly reduced hypothalamic MCH and orexin gene expression, this could not be restored by glucocorticoids in the drinking water. Collectively, the present data suggest that glucocorticoids may promote food intake in part by potentiating the orexigenic actions of MCH without affecting the actions of orexin A and that glucocorticoids act indirectly to influence the effects of MCH on food intake.
 ...
PMID:Differential effects of adrenalectomy on melanin-concentrating hormone and orexin A. 1504 62


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>