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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Progressive wasting is common in many types of cancer and is one of the most important factors leading to early death in cancer patients. Weight loss is a potent stimulus to food intake in normal humans and animals. The persistence of anorexia in cancer patients, therefore, implies a failure of this adaptive feeding response, although the weight loss in the patients differs from that found in simple starvation. Tremendous progress has been made in the last 5 years with regard to the regulation of feeding and body weight. It has been demonstrated that leptin, a hormone secreted by adipose tissue, is an integral component of the homeostatic loop of body weight regulation. Leptin acts to control food intake and energy expenditure via neuropeptidergic effector molecules within the hypothalamus. Complex interactions among the nervous, endocrine, and immune systems affect the loop and induce behavioral and metabolic responses. A number of cytokines, including tumor necrosis factor-alpha, interleukins 1 and 6, IFN-gamma, leukemia inhibitory factor, and ciliary neurotrophic factor have been proposed as mediators of the cachectic process. Cytokines may play a pivotal role in long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin. This could be done by persistent stimulation of anorexigenic neuropeptides such as corticotropin-releasing factor, as well as by inhibition of the neuropeptide Y orexigenic network that consists of opioid peptides and galanin, in addition to the newly identified melanin-concentrating hormone, orexin, and agouti-related peptide. Information is being gathered, although it is still insufficient, on such abnormalities in the hypothalamic neuropeptide circuitry in tumor-bearing animals that coincide with the development of anorexia and cachexia. Characterization of the feeding-associated gene products have revealed new biochemical pathways and molecular targets for pharmacological intervention that will likely lead to new treatments. Although therapeutic intervention using neuropeptide agonists/antagonists is now directed at obesity treatment, it may also have an effect on treating cancer anorexia-cachexia, especially when combined with other agents that have effects on muscle and protein breakdown.
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PMID:Cancer anorexia-cachexia syndrome: are neuropeptides the key? 1049 94

Orexins are recently identified neuropeptides, and have been shown to increase food intake when administered intracerebroventricularly. We examined the effects of chronic administration of orexin in rats by continuous intracerebroventricular administration by means of an osmotic minipump. Continuous administration of orexin-A (0.5 nmol/h) for 7 days in rats resulted in a significant increase in food intake in the daytime. Daytime food intake increased to 180% of the control value. However, it resulted in a slight decrease nighttime food intake as compared with vehicle-treated rats. The total amount of food intake per day was almost comparable with that of vehicle-administered rats. The gain of body weight and blood glucose, total cholesterol and free fatty acid levels were normal. Chronic orexin-A treatment did not cause obesity in rats. We observed abnormal behavior during the daytime after starting administration of orexin-A; these rats kept awake during the daytime. Our present observation showed that continuous administration of orexin-A could not overcome the regulation of energy homeostasis and body weight. However, orexin-A might be implicated in short-term, immediate regulation of feeding behavior.
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PMID:Chronic intracerebroventricular administration of orexin-A to rats increases food intake in daytime, but has no effect on body weight. 1059 11

Food intake is regulated via neural circuits located in the hypothalamus. During the past decade our knowledge on the specific mediators and neuronal networks that regulate food intake and body weight has increased dramatically. An important contribution to the understanding of hypothalamic control of food intake has been the characterization of the ob gene product (leptin) via positional cloning. Absence of circulating, functionally active, leptin hormone results in massive obesity as seen in ob/ob mice. Leptin inhibits food intake and increases energy expenditure via an interaction with specific leptin receptors located in the hypothalamus. Leptin receptors, of which there are several splice variants (Ob-Ra through Ob-Re), belong to the superfamily of cytokine receptors, which use the JAK-STAT pathway of signal transduction. Obese db/db mice, which have a mutation in the db locus, are unable to perform JAK-STAT signal transduction due to absence of functionally active (long form; Ob-Rb) leptin receptors. Ob-Rb is primarily expressed in the hypothalamus, with particularly high levels in the arcuate, paraventricular, and dorsomedial nuclei and in the lateral hypothalamic area. The abundance of leptin receptors in the ventromedial and lateral hypothalamus supports early observations that these two regions are intimately associated with the regulation of food intake. Leptin receptors have been identified in neuropeptide Y (NPY)/lagouti-related peptide (AgRP)- and proopiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART)-containing neurons of the ventromedial and ventrolateral arcuate nucleus, respectively, and in melanin-concentrating hormone (MCH)- and hypocretin/orexin-containing neurons of the lateral hypothalamus, suggesting that the above-mentioned messengers are mediators of leptin's action in the hypothalamus. Indeed, functional studies show that NPY, AgRP, POMC-derived peptides, CART, MCH, and hypocretins/orexins all are important regulators of food intake. Leptin is essential for normal body weight balance, but the exact mechanisms by which leptin activates hypothalamic neuronal circuitries is known to a limited extent. In order to find pharmaceutical approaches to treat obesity, further studies will be needed to reveal the exact mechanisms by which leptin lowers body weight and which role leptin and leptin receptors have in the pathogenesis of human obesity.
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PMID:Control of food intake via leptin receptors in the hypothalamus. 1071 43

The neuropeptides, monoamines and many drugs involved with modulating food intake and fat stores have reciprocal effects on sympathetic activity and thermogenesis. Both serotonin, acting through 5HT1B/2C receptors, and norepinephrine acting through beta2 and/or beta3 receptors reduce food intake and augment sympathetic activity. Neuropeptide Y, beta-endorphin, orexin, galanin and melanin concentrating hormone all increase food intake and, where tested, reduce sympathetic activity. In contrast, a larger number of peptides including cholecystokinin, corticotrophin-releasing hormone/urocortin, enterostatin, leptin, CART and alpha-MSH reduce food intake and increase sympathetic activity. Nicotine, prostaglandin, dexfenfluramine and sibutramine also have this reciprocal effect on feeding and sympathetic nervous system (SNS) activity. Chronic administration of neuropeptide Y (NPY) can produce chronically increased food intake and obesity. This syndrome is similar to the ventromedial hypothalamus (VMH) syndrome and suggests that NPY must be acting as an inhibitory signal to stimulate a feeding system and inhibit sympathetic activity. The melanocortin receptor system may be particularly important in modulating food intake, because a transgenic mouse which does not express melanocortin-4 receptors is massively overweight. Adrenal glucocorticoids are important in obesity since adrenalectomy will reverse or prevent the development of all forms of obesity. The clinical importance of the sympathetic nervous system and food intake is emphasized by the inverse relation of sympathetic activity and body fat. The inhibition of food intake, lower body fat stores and higher energy expenditure in smokers also support this hypothesis. The reciprocal relationship between food intake and sympathetic activity is robust, suggesting that beta receptors in the periphery and brain may be involved in the control of feeding and a reduction in food intake in humans accounts for most of the weight loss with ephedrine and caffeine. We conclude that the inhibition of feeding by activating the SNS is an important satiety system which helps regulate body fat stores.
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PMID:Reciprocal relation of food intake and sympathetic activity: experimental observations and clinical implications. 1099

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.
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PMID:The hypothalamus and the regulation of energy homeostasis: lifting the lid on a black box. 1099 54

A variety of evidence implicates the orexins, especially orexin-A, in the regulation of food intake, but it has not been established whether this effect is mediated by the orexin-1 or orexin-2 receptor. In the present study, a selective orexin-1 receptor antagonist, 1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-yl urea hydrochloride (SB-334867-A), was administered intraperitoneally to rats under various conditions, and food consumption was subsequently measured over 24 h. In male rats, a single dose of SB-334867-A (30 mg/kg, i.p.) given during the light phase reduced both orexin-A-induced food intake (7 nmol, i.c.v.) and feeding stimulated by an overnight fast for 4 h. When given at the start of the dark phase, food consumption was reduced in both male and female rats over 24 h. Daily injections at the start of the dark phase for 3 days reduced natural feeding in male rats over 24 h on days one and three. These findings demonstrate direct inhibition of orexin-A induced food intake with a selective orexin-1 receptor antagonist. Furthermore, the suppression of nocturnal feeding and food intake stimulated by an overnight fast supports other evidence that orexin-A is involved in the regulation of natural feeding and suggests that orexin-1 receptor antagonists could be useful in the treatment of obesity.
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PMID:A selective orexin-1 receptor antagonist reduces food consumption in male and female rats. 1110 51

Orexin A and B, also known as hypocretin 1 and 2, are two recently isolated hypothalamic peptides. As orexin-containing neurons are strategically located in the lateral hypothalamus, which has long been suspected to play an important role in feeding behaviors, initial studies were focused on the involvement of orexins in positive food intake and energy metabolism. Recent studies implicate a more diverse biological role of orexins, which can be manifested at different level of the neuraxis. For example, canine narcolepsy, a disorder with close phenotypic similarity to human narcolepsy, is caused by a mutation of hypocretin receptor 2 gene. Results from our immunohistochemical and functional studies, which will be summarized here, suggest that the peptide acting on neurons in the rostral ventrolateral medulla augment sympathoexcitatory outflow to the spinal cord. This finding is discussed in the context of increased sympathetic activity frequently associated with obesity.
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PMID:Orexins: a role in medullary sympathetic outflow. 1110 54

The lateral hypothalamic area (LHA) and the ventromedial hypothalamic nucleus (VMH) have historically been implicated in ingestive behavior, energy balance and body mass regulation. The LHA is more closely associated with the initiation of eating; whereas the VMH mediates the cessation of eating. The parvocellular part of the paraventricular nucleus (pPVN) is also included in the suppressing mechanism. Recently, two hypothalamic peptides, orexin-A and orexin-B, localized in the posterior and lateral hypothalamic perifornical region were discovered in the rat brain and they increase food intake. Leptin, a protein encoded by an obesity gene, expressed in adipose tissue and released into the blood also affects food intake. Orexin and leptin receptors have been localized in the LHA, pPVN, and VMH. The purpose of this study was to measure food intake in the rat in response to leptin and orexin-A; and to determine their electrophysiological effects on feeding related hypothalamic neurons. Results clearly show that leptin suppresses food intake whereas orexin-A increases food intake. These differences are associated with leptin and orexin-A modulatory effects on LHA, pPVN, and VMH glucose responding neurons. In the LHA, leptin inhibits a larger proportion of both glucose-sensitive neurons (GSNs) and non-GSNs. In the pPVN, leptin increases more GSNs in comparison to non-GSNs. Whereas in the VMH, leptin increases the activity of glucoreceptor neurons (GRNs) in comparison to non-GRNs. Orexin-A had opposite effects: increases activity of GSNs more than the non-GSNs in the LHA and significantly suppresses GRNs in the VMH. In the pPVN, orexin-A had no observable effects on neurons that have a low density of orexin 2 receptors. Results are discussed in terms of hypothalamic neural circuits that are sensitive to endogenous food intake inducing and reducing substances.
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PMID:Effects of leptin and orexin-A on food intake and feeding related hypothalamic neurons. 1115 May 56

An overweight patient (body mass index of 34 kg/m(2)) with narcolepsy associated with cataplexy is described. Polysomnography did not indicate obstructive sleep apnea. Her obesity was treated with sibutramine, a norepinephrine, serotonin and dopamine reuptake inhibiting medication and her severe cataplexy remitted. Clinicians must be aware that sibutramine may suppress cataplexy when evaluating excessive daytime sleepiness in an overweight patient taking this anti-obesity medication. Therefore a negative history of cataplexy in these cases may be misleading and narcolepsy may be overlooked in the differential diagnosis. Sibutramine should be discontinued before polysomnography and multiple sleep latency testing but may be a useful medication in the management of obese narcoleptic patients with cataplexy. With the discovery of decreased hypocretin 1 levels in humans with narcolepsy, a neuropeptide that modulates sleep and feeding, the association between narcolepsy and obesity requires more attention.
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PMID:Narcolepsy and obesity: remission of severe cataplexy with sibutramine. 1115 84

The primary role of the orexins was originally believed to be appetite regulation, but is now believed to be the regulation of sleep, arousal and locomotor activity. Orexin A immunoreactivity (orexin A-IR) and prepro-orexin mRNA were measured in the CNS of obese and lean Zucker rats. There were no differences in orexin A-IR or prepro-orexin mRNA levels between obese and lean Zucker rats. The orexins are therefore unlikely to be important in this model of obesity. Levels of orexin A-IR and prepro-orexin mRNA were measured in the CNS of Wistar-Kyoto (WKY) rats, which are hypoactive and have abnormal sleep architecture. Compared to Wistar rats, WKY rats had significantly lower orexin A-IR (with differences of up to 100% in some brain regions) and prepro-orexin mRNA levels. These observations suggest that the sleep and activity phenotype of the WKY strain may be related to orexin deficiency and that this strain may be a useful model of partial orexin deficiency.
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PMID:Orexin A immunoreactivity and preproorexin mRNA in the brain of Zucker and WKY rats. 1123 46


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