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

A review of evidence indicates that experimentally induced changes in the activity of serotonin (5-hydroxytryptamine) systems are associated with pronounced changes in feeding behaviour. In general, treatments and procedures believed to lead to an increased availability of 5-HT in the synaptic cleft or which directly activate 5-HT receptors reduce food consumption, while procedures which either directly or indirectly decrease 5-HT receptor activation bring about the opposite effect. Interpretation of findings is hindered by methodological difficulties involved in the experimental manipulation of serotonin metabolism, by the lack of precise behavioural measures of feeding, and by the presence of large stores of serotonin outside the brain. However, available data favour the idea that serotonin systems play an inhibitory role in feeding, possibly in the mediation of satiety. This proposal has implications for further experimental investigations of the control of food intake, and for the aetiology and treatment of obesity.
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PMID:Is there a role for serotonin (5-hydroxytryptamine) in feeding? 36 84

Recent progress in the molecular pharmacology of 5-HT receptors and the development of selective ligands for various 5-HT receptor subtypes has advanced our understanding of the role of 5-HT mechanisms in the control of food intake and bodyweight. The most intensively investigated 5-HT receptor subtypes have been the 5-HT1A receptor, the 5-HT1B receptor and the 5-HT2C receptor. The overall pattern of results to date suggests that selective 5-HT2C agonists may be novel anorectic drugs and prove useful in the treatment of obesity. However, a number of issues remain unresolved, particularly regarding potential side-effects, as the 5-HT2C receptor agonist mCPP has been reported to induce anxiety and nausea in humans, actions that would clearly limit its therapeutic utility. In addition, the possible role of recently cloned 5-HT receptor subtypes such as 5-ht5, 5-ht6 and 5-ht7, remains unexplored and the development of selective ligands for these sites has the potential to lead to new treatments for obesity.
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PMID:Multiple serotonin receptors: opportunities for new treatments for obesity? 869 43

5-Hydroxytryptamine (5-HT) is a mediator of chloride ion (Cl-) secretion in the intestine which can be seen as a rise in short circuit current (Isc) in the Ussing chamber model. We investigated the 5-HT receptor mediating 5-HT-induced Cl- secretion in the human jejunum in vitro. Jejunal segments obtained from patients having gastric bypass surgery for obesity, were stripped of muscularis and mounted in Ussing chambers and short-circuited. The 5-HT receptor agonist-induced change (delta) in Isc was recorded in the presence and and absence of 5-HT receptor antagonists. The rank order of agonist potency was: 5-HT > 5-methoxytryptamine > renzapride (BRL 24924 > alpha-methyl-5-HT >> 2-methyl-5-HT. In the presence of Cl(-)-free media or 100 microM furosemide, 5-HT-induced delta Isc was significantly reduced. It was also antagonized by > or = 1 microM tropisetron (a 5-HT 3/5-HT4 receptor antagonist) and > or = 10 nM GR 113808 (a selective 5-HT4 receptor antagonist) with pA2 values of 6.5 and 7.9, respectively. Another 5-HT4 receptor antagonist, SC 53606 (0.1 microM), antagonized the 5-HT-induced response with a pA2 of 7.3 5-HT1-like/5-HT2 (methysergide), 5-HT1P [N-acetyl-5-hydroxytryptophyl 5-hydroxytryptophan amide (5-HT-DP], 5-HT2A (ketanserin) and 5-HT3 (ondansetron) receptor antagonists and tetrodotoxin, had no significant effect on the EC50 for 5-HT. In conclusion, this study demonstrates that in the human muscle-stripped jejunum in vitro, 5-HT induced change in short circuit current is mediated by a 5-HT4 receptor via a non-neural pathway.
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PMID:The role of the 5-HT4 receptor in Cl- secretion in human jejunal mucosa. 895 25

Serotonin is a neurotransmitter involved in a large number of psychophysiological processes including the regulation of mood, arousal, aggression, sleep, learning, nociceptions, nerve growth and importantly, appetitive functions. Alterations of 5-HT receptor activity have been shown to occur in many psychiatric diseases including depression, anxiety, eating disorders, schizophrenia etc. Hence, genetic variation in genes coding for serotonin receptor proteins might well be involved in the genetic predisposition to these diseases and therefore are of great pharmacogenetic relevance. Knockout mice deficient of a functional 5-HT2C receptor have implicated a potential role of this receptor subtype in the serotonergic control of appetite. A Cys23Ser mutation in the human 5-HT2C receptor gene discovered recently prompted us to investigate this mutation with regard to the development of human obesity. We have evaluated this mutation in 241 obese children and adolescents (mean BMI > or = 97th percentile), 80 normal weight children (BMI 5th-85th percentile) and 92 underweight probands (BMI < or = 15th percentile) for a possible association with obesity. The frequencies of the mutant allele in all three weight groups (obese subjects: 0.1597; normal weight: 0.168; underweight: 0.1575) were very similar. Association as well as linkage studies were negative. Therefore it is unlikely that this receptor mutation plays a direct role in the development of human obesity.
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PMID:Evaluation of a Cys23Ser mutation within the human 5-HT2C receptor gene: no evidence for an association of the mutant allele with obesity or underweight in children, adolescents and young adults. 920 Jun 73

1. Sibutramine is a novel 5-hydroxytryptamine (5-HT) and noradrenaline reuptake inhibitor (serotonin-noradrenaline reuptake inhibitor, SNRI) which is currently being developed as a treatment for obesity. Sibutramine has been shown to decrease food intake in the rat. In this study we have used a variety of monoamine receptor antagonists to examine the pharmacological mechanisms underlying sibutramine-induced hypophagia. 2. Individually-housed male Sprague-Dawley rats were maintained on reversed phase lighting with free access to food and water. Drugs were administered at 09 h 00 min and food intake was monitored over the following 8 h dark period. 3. Sibutramine (10 mg kg-1, p.o.) produced a significant decrease in food intake during the 8 h following drug administration. This hypophagic response was fully antagonized by the alpha 1-adrenoceptor antagonist, prazosin (0.3 and 1 mg kg-1, i.p.), and partially antagonized by the beta 1-adrenoceptor antagonist, metoprolol (3 and 10 mg kg-1, i.p.) and the 5-HT receptor antagonists, metergoline (non-selective; 0.3 mg kg-1, i.p.); ritanserin (5-HT2A/2C; 0.1 and 0.5 mg kg-1, i.p.) and SB200646 (5-HT2B/2C; 20 and 40 mg kg-1, p.o.). 4. By contrast, the alpha 2-adrenoceptor antagonist, RX821002 (0.3 and 1 mg kg-1, i.p.) and the beta 2-adrenoceptor antagonist, ICI 118,551 (3 and 10 mg kg-1, i.p.) did not reduce the decrease in food intake induced by sibutramine. 5. These results demonstrate that beta 1-adrenoceptors, 5-HT2A/2C-receptors and particularly alpha 1-adrenoceptors, are involved in the effects of sibutramine on food intake and are consistent with the hypothesis that sibutramine-induced hypophagia is related to its ability to inhibit the reuptake of both noradrenaline and 5-HT, with the subsequent activation of a variety of noradrenaline and 5-HT receptor systems.
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PMID:Investigation of the mechanisms underlying the hypophagic effects of the 5-HT and noradrenaline reuptake inhibitor, sibutramine, in the rat. 928 94

5-Hydroxytryptamine (5-HT, serotonin), synthesized in midbrain raphe nuclei and released in various hypothalamic sites, decreases food intake but the specific 5-HT receptor subtypes involved are controversial. Here, we have studied changes in the regional density of binding to 5-HT receptors and transporters and the levels of tryptophan hydroxylase, in rats with obesity induced by feeding a palatable high-energy diet for 7 weeks. We mapped binding at 5-HT receptor subtypes and transporters using quantitative autoradiography and determined tryptophan hydroxylase protein levels by Western blotting. In diet-induced obese (DiO) rats, specific binding to 5-HT(1A) receptors ([3H]8-OH-DPAT) was significantly increased in the dorsal and median raphe by 90% (P<0.01) and 132% (P<0.05), respectively, compared with chow-fed controls. 5-HT(1B) receptor binding sites ([125I]cyanopindolol) were significantly increased in the hypothalamic arcuate nucleus (ARC) of DiO rats (58%; P<0.05), as were 5-HT(2A) receptor binding sites ([3H]ketanserin) in both the ARC (44%; P<0.05) and lateral hypothalamic area (LHA) (121%; P<0.05). However, binding to 5-HT(2C) receptors ([3H]mesulgergine) in DiO rats was not significantly different from that in controls in any hypothalamic region. Binding to 5-HT transporters ([3H]paroxetine) was significantly increased (P<0.05) in both dorsal and median raphe, paraventricular nuclei (PVN), ventromedial nuclei (VMH), anterior hypothalamic area (AHA) and LHA of DiO rats, by 47%-165%. Tryptophan hydroxylase protein levels in the raphe nuclei were not significantly different between controls and DiO rats. In conclusion, we have demonstrated regionally specific changes in binding to certain 5-HT receptor subtypes in obesity induced by voluntary overeating of a palatable diet. Overall, these changes are consistent with reduced 5-HT release and decreased activity of the 5-HT neurons. Reduction in the hypophagic action of 5-HT, possibly acting at 5-HT(1A), 5-HT(1B) and 5-HT(2A) receptors, may contribute to increased appetite in rats presented with highly palatable diet.
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PMID:Increased binding at 5-HT(1A), 5-HT(1B), and 5-HT(2A) receptors and 5-HT transporters in diet-induced obese rats. 1056 40

An association between the brain serotonin (5-HT) system and feeding has been postulated since the 1970's but it has only been in recent years that the nature of 5-HT-mediated hypophagia has become well understood, and the receptor subtypes responsible for the effect better defined. The invention and utilisation of subtype-selective 5-HT receptor antagonists has demonstrated that the 5-HT(2C) receptor is of paramount importance in this regard. Importantly, ethological studies of animal behaviour have shown that the hypophagia resulting from 5-HT(2C) receptor activation is likely to be a consequence of increased satiety and this is in contrast to hypophagia following 5-HT(2A) receptor activation. Furthermore, recent studies have also shown that 5-HT(2C) receptor agonists not only reduce feeding when acutely administered to rats or mice, they can also reduce body weight without inducing tolerance when administered chronically to obese animals. These observations have led researchers to conclude that selective 5-HT(2C) receptor agonists have the potential to be effective anti-obesity agents. Encouragingly, this suggestion is supported by both direct and indirect evidence from clinical studies. Indirect evidence stems from recent observations that the clinically effective anorectic agent d-fenfluramine exerts its hypophagic and weight-loss effects via 5-HT(2C) receptor activation. More direct clinical evidence derives from the use of the prototypical 5-HT(2C) receptor agonist m-chlorophenylpiperazine (mCPP), with which both acute hypophagia and body-weight loss have been observed. The current paper therefore reviews both the pre-clinical and clinical evidence supporting the use of 5-HT(2C) receptor agonists for the treatment of obesity and assesses the developments that have been made in this regard to date.
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PMID:5-HT2C receptor agonists as potential drugs for the treatment of obesity. 1267 38

The anorexigen (+)-fenfluramine was used for treatment of obesity until the association of use with valvular heart disease and primary pulmonary hypertension. (+)-Fenfluramine has been found in Chinese and Korean slimming pills. The hepatic metabolite of (+)-fenfluramine, (+)-norfenfluramine, has affinity for 5-hydroxytryptamine (5-HT)(2A) and 5-HT(2B) receptors. We tested the hypothesis that (+)-norfenfluramine contracts arterial smooth muscle in a 5-HT receptor-dependent manner and acts as a pressor in the conscious rat. Isometric contraction experiments showed that (+)-norfenfluramine (10 nM, 100 microM) but not (+)-fenfluramine nor the isomer (-)-norfenfluramine caused concentration-dependent contraction in arteries [-log EC(50) (moles per liter), thoracic aorta = 5.77 +/- 0.09; renal artery = 6.29 +/- 0.02; mesenteric resistance artery = 5.70 +/- 0.06]. Contraction was dependent on the 5-HT(2A) receptor because ketanserin (10 nM) rightward shifted (+)-norfenfluramine response curves (aorta = 16-fold, renal artery = 26-fold, and resistance artery = >100-fold). Dependence on activation of 5-HT(2A) receptors and independence of (+)-norfenfluramine-induced contraction from stimulation of alpha-adrenergic receptors and the sympathetic nervous system was validated by demonstrating 1) unchanged contraction to (+)-norfenfluramine in arteries from chemically denervated rats; 2) a minimal effect of the alpha(1)-adrenergic receptor antagonist prazosin (100 nM) on contraction; and 3) antagonism by [6-methyl-l-(1-methylethy)ergoline-8beta-carboxylic acid 2-hydroxy-1 methylpropyl ester maleate] LY53857 [6-methyl-1-(1-methylethy)-ergoline-8beta-carboxylic acid 2-hydroxy-1 methylpropyl ester maleate], a 5-HT(2) receptor antagonist without alpha-receptor affinity. (+)-Norfenfluramine (10-300 microg/kg i.v.) caused a dose-dependent increase in mean arterial blood pressure in conscious rats, the maximum of which could be virtually abolished by ketanserin (3 mg/kg i.v.) but not prazosin (0.2 mg/kg i.v.). Our findings demonstrate for the first time that (+)-norfenfluramine is vasoactive and has the potential to increase blood pressure.
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PMID:The fenfluramine metabolite (+)-norfenfluramine is vasoactive. 1475 59

It was first established in the 1970s that the brain serotonin (5-HT) system was involved in the control of eating. Subsequent progress in the molecular pharmacology of 5-HT receptors, and the development of selective 5-HT receptor ligands, has clarified our understanding of the role of 5-HT in the regulation of ingestive behavior. Of the 14 5-HT receptor subtypes currently described, 5-HT1A, 5-HT1B and 5-HT2C receptors have been of principal interest in the regulation of food intake. This is largely due to the development of suitable agonists, antagonists and gene-knockout animals with which the role of these receptors can be elucidated. The recent development of selective ligands and knockout mice for other 5-HT receptors, including the 5-HT2B and 5-HT6 receptors, has also suggested a role for these receptor subtypes in eating behavior. Studies using such approaches should further our understanding of the role of serotonin in the regulation of feeding behavior and thus, may lead to the development of novel, safe, serotonin receptor ligands for the treatment of obesity.
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PMID:Serotonin receptor ligands and the treatment of obesity. 1513 78

The anti-obesity effect of the serotonin and noradrenaline reuptake inhibitor sibutramine has been attributed to a dual mechanism involving a reduction of food intake and an increase in energy expenditure. This dual action increases the possibilities for induction of a negative energy balance, the principal goal of an anti-obesity treatment. To elucidate the mechanism behind sibutramine-induced increase in energy expenditure, we applied indirect calorimetry combined with monitoring locomotor activity and body temperature. We confirm that sibutramine has both anorectic and thermogenic effects. In addition, we show here that sibutramine also causes a dose-dependent increase in locomotor activity (LMA) of rats, occurring in parallel with increase in energy expenditure. The dose of sibutramine necessary to induce an effect on locomotion and energy expenditure was only marginally higher than the dose sufficient to induce a significant reduction of food intake. The relation between LMA and energy expenditure was similar to that found with d-amphetamine, which causes both hyper-locomotion and increased energy expenditure, but was different from 2,4-dinitrophenol which causes increase in energy expenditure but not in locomotion. The effect of sibutramine (20 mg/kg) on energy expenditure was not inhibited by the non-selective 5-HT receptor antagonist, metergoline (1 mg/kg), or a high dose (20 mg/kg) of the non-selective beta-blocker propranolol, but was blocked by D1 dopamine receptor inhibitor SCH 23390 (0.3 mg/kg). Therefore, we conclude that the effect of sibutramine on energy expenditure in rats is predominantly due to a dopamine-dependent increase in locomotor activity.
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PMID:Locomotion is the major determinant of sibutramine-induced increase in energy expenditure. 1664 8


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