UMLS:C0028754 - FACTA Search

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

Past studies have indicated that genetically obese Zucker (fa/fa) rats are hypercorticoid, and that this neuroendocrine alteration plays a key role in the syndrome. In keeping with the proposal that glucocorticoids may upregulate central 5-HT2A receptors, we have studied the effects of acute and repeated 5-HT2A receptor stimulation by 1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane (DOI) in lean and obese Zucker rats. Acute injection of DOI (2 mg/kg, SC) elicited a lower number of head shakes in obese rats compared to that measured in lean rats. Conversely, neither DOI-elicited decreases in food intakes and body weights nor cortical [3H]ketanserin binding were affected by obesity. In rats repeatedly pretreated with DOI, biochemical and functional indices of 5-HT2A receptor downregulation failed to reveal an effect of obesity. It is suggested that 5-HT2A receptor-mediated functions, but not their downregulation, may be differentially affected in the hypercorticoid obese Zucker rat.
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PMID:Cortical [3H]ketanserin binding and 5-HT2A receptor-mediated behavioral responses in obese Zucker rats. 774 73

We have attempted to provide a progress report on current research on the role of catecholamines and serotonin receptor subtypes in feeding control. Recent evidence suggests that only some of the several catecholamine receptor subtypes are specifically involved in feeding control. They include the beta 1/2-adrenoceptors, the alpha 1-adrenoceptors and the D1 dopamine receptors: stimulation of these receptors reduces feeding in rats. Stimulation of serotonergic 5-HT1B and 5-HT2C receptors reduces feeding and perhaps enhances the satiating effect of food. Recently, an interesting reciprocal relation between serotonin and cholecystokinin has been discovered in relation to feeding control. The serotonergic 5-HT2A receptors are involved in stress-induced anorexia and regulate the hyperphagia induced by neuropeptide Y in the nucleus paraventricularis of the hypothalamus. Both effects may involve changes in the secretion of corticotropin-releasing factor. These findings may help elaborate neuronal models of feeding control and perhaps facilitate progress in the pharmacotherapy of human obesity and eating disorders.
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PMID:Pharmacology of ingestive behaviour. 876 44

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

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

D-Fenfluramine is a serotonin (5-hydroxytryptamine, 5-HT) releaser and reuptake inhibitor. It is used to study the neurochemical control of feeding and has been used to treat obesity. It has also been employed as a pharmacological tool to study changes in serotonergic function in psychiatric patients. Brain sites activated by D-fenfluramine via the release of 5-HT have been mapped via the expression of the immediate early gene c-fos. Studies in our laboratory have indicated that D-fenfluramine induces Fos in the hypothalamus and cortex through 5-HT release. The present study investigated whether 5-HT released by D-fenfluramine induces Fos expression in the brain by activating 5-HT1A or 5-HT2A/2C receptors. Rats were pretreated either with WAY-100635, a 5-HT1A antagonist, or ritanserin, a 5-HT2A/2C antagonist, prior to d-fenfluramine injection. Blockade of either 5-HT1A or 5-HT2A/2C receptors was not sufficient to suppress the Fos response to D-fenfluramine in any region of the brain examined, including the cingulate cortex, frontal cortex, caudate-putamen, paraventricular nucleus of the hypothalamus, amygdala, and brainstem. These results indicate that Fos response elicited by D-fenfluramine may be mediated by other receptors, in addition to the 5-HT1A or 5-HT2A/2C receptors.
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PMID:The 5-HT1A and 5-HT2A/2C receptor antagonists WAY-100635 and ritanserin do not attenuate D-fenfluramine-induced fos expression in the brain. 959 27

Elemental chromium (Cr) is an essential micronutrient. It is required for optimal insulin activity and normal carbohydrate and lipid metabolism. Tri-valent chromium (Cr3+) is recommended for the treatment of diabetes and obesity. There is evidence that Cr3+ may have antidepressant properties, possibly by enhancement of monoamine function through its ability to increase amino acid transport to the brain. The aim of the present study was to investigate further the possible effects of Cr3+ treatment on peripheral amino acid availability and brain monoamine function in the rat. We undertook three studies in rats. The first was a time-course study in which animals were administered single doses of 50 mg/kg of Cr3+ picolinate and the second a dose-response study in which animals were given either 20 or 50 mg/kg Cr3+ picolinate versus vehicle alone via the intra-peritoneal route. In the third, animals were fed a diet containing Cr3+ picolinate (100 mg/kg) or a similar control diet for two weeks and were then sacrificed. Blood was sampled and brains were removed for later analysis. Results from the Cr3+ time-course study defined an optimal time for sampling of two hours after dosing. Results from the second study showed dose-related responses to Cr3+ treatment for a number of measured biochemical parameters including serum corticosterone. In the sub-chronic treatment study Cr3+ significantly increased serum free tryptophan (TRP), non-esterified free fatty acids (NEFFAs), corticosterone, together with brain TRP, serotonin (5-hydroxytryptamine, 5-HT), noradrenaline (NA) and pineal melatonin. From other studies in our laboratory we have shown that Cr3+ treatment can modify brain 5-HT function, perhaps by altering the sensitivity of central 5-HT2A receptors. The peripheral effect of Cr3+ picolinate treatments and their consequential central effect on increased serotonergic and noradrenergic function may suggest that Cr3+ could have some antidepressant-like actions. Future studies to confirm this are to be done.
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PMID:Effects of treatment with chromium picolinate on peripheral amino acid availability and brain monoamine function in the rat. 1535 78

This prospective cohort study in Japanese workers examined the relationship between the -1438A/G polymorphism in the 5-hydroxytryptamine receptor 2A gene and the development of positive findings for various life-style-related disorders. This study over the 5-year period, 1997-2002, included observations of several disorders in cohorts ranging between 560-1023 for males and 477-735 for females who had negative findings for each disorder at baseline. The criteria for development of the disorders were: hypertension, systolic blood pressure > or =140 mmHg or dia-stolic blood pressure > or =90 mmHg or taking antihypertensive medication; overweight, body mass index (BMI) > or =25 kg/m(2); obesity, BMI > or =30 kg/m(2); new onset of cerebral stroke; metabolic abnormalities, glycosylated hemoglobin A1c >6.0%, total cholesterol > or =240 mg/dl, high-density lipoprotein cholesterol <40 mg/dl, uric acid >7.0 mg/dl, gamma-glutamyl transpeptidase > or =60 IU/l in males and > or =30 IU/l in females. Pooled logistic regression analyses were performed using the -1438A/G genotype and other potential factors as covariates. The odds ratios to AA genotype were significant for uric acid (GG, 0.52; AG, 0.59), obesity (AG, 0.24) in males and for high-density lipoprotein cholesterol (GG, 0.11; AG, 0.36), gamma-glutamyl transpeptidase (GG, 0.53; AG, 0.62) and total cholesterol (GG, 1.84) in females. The present study is the first prospective cohort investigation to demonstrate that the -1438G allele has a protective effect against the development of a range of cardiovascular and metabolic disorders. This study indicates that the -1438A/G polymorphism is an independent factor for various disorders in the general Japanese population and suggests that targeting of this polymorphism may be beneficial for preventing these disorders in Japan.
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PMID:The -1438A/G polymorphism in the 5-hydroxytryptamine receptor 2A gene is related to hyperuricemia, increased gamma-glutamyl transpeptidase and decreased high-density lipoprotein cholesterol level in the Japanese population: a prospective cohort study over 5 years. 1632 14

WAY-161503 ((4aR)-8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one), a 5-HT(2B/C) receptor agonist, was characterized in vitro using stable Chinese hamster ovary cell lines expressing each of the human 5-HT2 receptors and in vivo in animal models of obesity. WAY-161503 displaced both agonist ([125I]2,5-dimethoxy-4-iodoamphetamine (DOI)) and antagonist ([3H]mesulergine) radioligand binding to the human 5-HT2C receptor with derived Ki values of 3.3 +/- 0.9 and 32 +/- 6 nM, respectively. Relative to 5-HT2C receptor binding, WAY-161503 was approximately 6-fold less potent at human 5-HT2A receptors ([125I]DOI) with a derived Ki value of 18 nM and 20-fold less potent at human 5-HT2B receptors ([3H]5-HT) with a derived Ki value of 60 nM. In functional studies, WAY-161503 was a full agonist in stimulating 5-HT2C-receptor-coupled [3H]inositol phosphate (IP) formation and calcium mobilization with EC50 values of 8.5 nM and 0.8 nM, respectively. WAY-161503 was also a 5-HT2B agonist (EC50s of 6.9 and 1.8 nM for IP and calcium, respectively). In IP studies, WAY-161503 was a weak 5-HT(2A) partial agonist (EC50, 802 nM) yet potently stimulated calcium mobilization (EC50, 7 nM) in 5-HT2A receptor-expressing cells. Functionally, WAY-161503 also stimulated the phospholipase A2-coupled arachidonic acid release in 5-HT2C receptor expressing cells albeit with lower potency (EC50, 38 nM) and efficacy (Emax, 77%) compared with activation of the PLC pathway. In vivo, WAY-161503 produced dose-dependent decreases in 2-h food intake in 24 h fasted normal Sprague-Dawley rats, diet-induced obese mice, and obese Zuker rats with ED50 values of 1.9 mg/kg, 6.8 mg/kg, and 0.73 mg/kg, respectively. The reduction in food intake in normal Sprague-Dawley rats was reversed by administration of the 5-HT2C receptor antagonist SB-242084. Following chronic administration (10 days) in growing Sprague-Dawley rats, WAY-161503 decreased food intake and attenuated body weight gain. Finally, following chronic administration (15 days) of WAY-161503 to obese Zuker rats, the rats maintained a 30% decrease in food intake over the 15-day period combined with a 25 g decrease in body weight relative to vehicle-treated controls demonstrating a lack of tolerance to its anorectic effects.
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PMID:Antiobesity-like effects of the 5-HT2C receptor agonist WAY-161503. 1643 Aug 74

The serotonin (5-hydroxytryptamine) 5-HT2 receptor subfamily consists of three members, 5-HT2A, 5-HT2B, and 5-HT2C. These receptors share high homology in their amino acid sequence, have similar signaling pathways, and have been indicated to play important roles in feeding, anxiety, aggression, sexual behavior, mood, and pain. Subtype-selective agonists and antagonists have been explored as drugs for hypertension, Parkinson's disease, sleep disorders, anxiety, depression, schizophrenia, and obesity. In this study, we report the development of homogeneous agonist binding assays in a scintillation proximity assay (SPA) format to determine the high-affinity binding state of agonist compounds for the human 5-HT2C, 5-HT2A, and 5-HT2B receptors. The 5-HT2 agonist 1-(4- [125I]iodo-2,5-dimethoxyphenyl)-2-aminopropane ([125I]DOI) was used to label the high-affinity sites for the 5-HT2A and 5-HT2C receptors. The high-affinity sites for the 5-HT2B receptor were labeled with [3H]lysergic acid diethylamide. Total receptor expression was determined with the 5-HT2 antagonist [3H]mesulergine for the 5-HT2B and 5-HT2C receptors, and [3H]ketanserin for the 5-HT2A receptor. The agonist high-affinity binding sites accounted for 2.3% (5-HT(2C) receptor), 4.0% (5-HT2A receptor), and 22% (5-HT2B receptor) of the total receptor population. Competition binding studies using known agonists indicated high Z' values of the agonist binding assays in SPA format (Z' > 0.70). The Ki values of 5-HT, (R)(-)DOI, and VER-3323 for the 5-HT2A, 5-HT2B, and 5-HT2C receptors by SPA format were equivalent to published data determined by filtration binding assays. These results indicate that agonist binding assays in SPA format can be easily adapted to a high throughput assay to screen for selective 5-HT2C receptor agonists, as well as for selectivity profiling of the compounds.
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PMID:Development of homogeneous high-affinity agonist binding assays for 5-HT2 receptor subtypes. 1643 60

Serotonin has been related to feeding behaviour and body weight control through its suppressive effect on appetite. Conflicting results have been published in the literature regarding the association between the - 1438 G/A promoter polymorphism of the 5HT2A gene with obesity-related variables. The aim of this study was to assess the association between the--1438 G/A polymorphism of the 5HT2A gene with childhood obesity in a Spanish population. A total of 136 cases aged 6-16 years with BMI above the 97th percentile of the Spanish BMI reference data for age and gender were matched by gender and age (+/- 6 months) with 136 controls. Additionally, 43 obese children and their parents were selected for a family-based association study (case-parent study). Genotyping was carried out by polymerase chain reaction and restriction enzyme analysis. Conditional logistic regression and transmission/disequilibrium test were used to assess genotype-obesity association. In the matched case-control study, the crude and adjusted odds ratios for the association between 5HT2A--1438 G/A genotypes were nonsignificant. Likewise, no association is suggested by the case-parent study. In conclusion, it is unlikely that the--1438 G/A polymorphism of 5HT2A gene may influence obesity in a Spanish children population.
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PMID:No evidence of association between the serotonin 2A receptor--1438G/A promoter polymorphism and childhood obesity in a Spanish population: A case-parent study and a matched case-control study. 1649 45

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