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 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.
 ...
PMID:Pharmacology of ingestive behaviour. 876 44

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.
 ...
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

The neurotransmitter serotonin is known to play a key role in determining emotional state in higher animals, especially in humans. Pharmacological studies have highlighted a subset of serotonin receptor subtypes (1A, 2B and 2C) worthy of knockout analysis. Several groups investigated knockout phenotype and determined the physiological function of these receptors, although the phenotype of the mouse seems somewhat paradoxical. However, the results strongly suggest that serotonin receptors are mainly involved in emotion (i.e., anxiety, aggressive behavior, obesity and epilepsy).
 ...
PMID:[Serotonin receptor knockout mice]. 1080 9

In the present study, we examined the potential impact of the 5-HT(2A) -1438G/A promoter polymorphism on obesity and estimates of insulin, glucose, and lipid metabolism as well as circulating hormones, including salivary cortisol, in 284 unrelated Swedish men born in 1944. The subjects were genotyped by using PCR amplification of the promoter region of the gene for 5-HT(2A) followed by digestion with the restriction enzyme MspI. The frequencies were 0.39 for allele -1438A and 0.61 for allele -1438G. Homozygotes for the -1438G allele had, in comparison with -1438A/A subjects, higher body mass index (BMI), waist-to-hip ratio (WHR), and abdominal sagittal diameter. Moreover, cortisol escape from 0.25 mg dexamethasone suppression was found in subjects with the -1438A/G genotype. Serum leptin, fasting insulin and glucose, as well as serum lipids were not different across the -1438G/A genotype groups. From these results, we suggest the possibility that an abnormal production rate of the 5-HT(2A) gene product might lead to the development of abdominal obesity. The pathophysiology could involve stress factors that destabilize the serotonin-hypothalamic-pituitary-adrenal systems in those with genetic vulnerability in the serotonin receptor gene.
 ...
PMID:Increased abdominal obesity in subjects with a mutation in the 5-HT(2A) receptor gene promoter. 1207 91

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.
 ...
PMID:Serotonin receptor ligands and the treatment of obesity. 1513 78

Deletion of the serotonin receptor 5HT2c in mice results in increased food intake and obesity. We screened 95 individuals with severe early-onset obesity for mutations in the coding sequence of this gene. We found a novel missense variant c.1255A > G (Thr419Ala) in a single Caucasian subject that was not found in 192 Caucasian control subjects. In transiently-transfected COS cells, the Thr419Ala variant was indistinguishable from the wild-type receptor in its ability to generate inositol phosphate, although differences in coupling to other pathways were not excluded. Three previously unreported silent variants: IVS3 + 30G > A, IVS3 + 80C > G and IVS4 - 31A > G were found with prevalences of 11.5%, 0.5% and 17.9%, respectively. In conclusion, mutations in 5HT2c are unlikely to be a common cause of severe early-onset human obesity. The identification of several novel polymorphisms at this locus may aid future genetic epidemiological studies.
 ...
PMID:Mutational analysis of the serotonin receptor 5HT2c in severe early-onset human obesity. 1538 68

The serotonin, norepinephrine, dopamine, and endocannabinoid systems, as well as a host of other systems, mediate hunger and satiety signals. Weight loss agents that modulate appetite through pure central nervous system pathways (e.g., APD356, a selective serotonin receptor agonist) and peripheral signals to central nervous system pathways (e.g., cholecystokinin receptor agonists and ghrelin receptor antagonists) are in preclinical or early phase studies. Both devices and pharmacological compounds that facilitate weight loss and/or target multiple components of metabolic risk also are in development. One of the medications that has completed extensive phase III clinical trials and may become available in the foreseeable future is rimonabant, a selective cannabinoid 1-receptor antagonist. Drugs that improve adipose tissue function or fatty acid metabolism (e.g., AOD9604) also are in clinical trials. Some currently available medications may reduce metabolic complications without treating obesity per se (e.g., acipimox, pioglitazone). Surgically implanted gastric pacemaker systems that modulate vagus nerve activity and delay gastric emptying are under study.
Obesity (Silver Spring) 2006 Jun
PMID:Potential role of new therapies in modifying cardiovascular risk in overweight patients with metabolic risk factors. 1693 96

Over 35 years of research suggests that endogenous hypothalamic serotonin (5-hydroxytryptamine) plays an important part in within-meal satiation and post-meal satiety processes. Thus, the serotonin system has provided a viable target for weight control, critical to the action of at least two effective anti-obesity treatments, both producing clinically significant weight loss over a year or more. Numerous serotonin receptor subtypes have been identified; of these, serotonin 5-HT1B and 5-HT2C receptors have been specifically recognised as mediators of serotonin-induced satiety.A number of serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs), dexfenfluramine and 5-HT2C receptor agonists, have been shown to significantly attenuate rodent bodyweight gain. This effect is strongly associated with marked hypophagia and is probably mediated by the hypothalamic melanocortin system. Additionally, sibutramine, dexfenfluramine, fluoxetine and the 5-HT2C receptor agonist chlorophenylpiperazine (mCPP) have all been shown to modify appetite in both lean and obese humans, resulting in reduced caloric intake. Clinical studies demonstrate serotonergic drugs specifically reduce appetite prior to and following the consumption of fixed caloric loads, and cause a reduction in pre-meal appetite and caloric intake at ad libitum meals. Weight loss in the obese has also been produced by treatment with both the serotonin precursor 5-hydroxytryptophan and the preferential 5-HT2C receptor agonist mCPP.A new generation of 5-HT2C receptor selective agonists have been developed and at least one, lorcaserin (APD356), is currently undergoing clinical trials. In addition, 5-HT6 receptor antagonists such as PRX-07034 and BVT74316 have been shown to potently reduce food intake and bodyweight gain in rodent models and have recently entered clinical trials. However, the role of the 5-HT6 receptor in the expression of appetite remains to be determined. The hope is that these drugs will not only be free of their predecessors' adverse effect profiles, but will also be equally or more effective at regulating appetite and controlling bodyweight.
 ...
PMID:Serotonergic drugs : effects on appetite expression and use for the treatment of obesity. 1720 63

Prader-Willi syndrome (PWS) is caused by loss of function of paternally expressed genes in the 15q11-q13 region and a paucity of data exists on transcriptome variation. To further characterize genetic alterations in this classic obesity syndrome using whole genome microarrays to analyze gene expression, microarray and quantitative RT-PCR analysis were performed using RNA isolated from lymphoblastoid cells from PWS male subjects (four with 15q11-q13 deletion and three with UPD) and three age and cognition matched nonsyndromic comparison males. Of more than 47,000 probes examined in the microarray, 23,383 were detectable and 323 had significantly different expression in the PWS lymphoblastoid cells relative to comparison cells, 14 of which were related to neurodevelopment and function. As expected, there was no evidence of expression of paternally expressed genes from the 15q11-q13 region (e.g., SNRPN) in the PWS cells. Alterations in expression of serotonin receptor genes (e.g., HTR2B) and genes involved in eating behavior and obesity (ADIPOR2, MC2R, HCRT, OXTR) were noted. Other genes of interest with reduced expression in PWS subjects included STAR (a key regulator of steroid synthesis) and SAG (an arrestin family member which desensitizes G-protein-coupled receptors). Quantitative RT-PCR for SAG, OXTR, STAR, HCRT, and HTR2B using RNA isolated from their lymphoblastoid cells and available brain tissue (frontal cortex) from separate individuals with PWS and control subjects and normalized to GAPD gene expression levels validated our microarray gene expression data. Our analysis identified previously unappreciated changes in gene expression which may contribute to the clinical manifestations seen in PWS.
 ...
PMID:Whole genome microarray analysis of gene expression in Prader-Willi syndrome. 1723 94

Obesity is a complex disease, which in many cases appears as a polygenic condition affected by environmental factors (mainly unbalanced dietary patterns and physical inactivity). In this context, the weight loss response to dietary interventions varies widely and predictive factors of successful slimming including those concerned with the individual's genetic make-up are poorly understood. Indeed, a number of genes involved in the regulation of energy expenditure, appetite, lipid metabolism and adipogenesis have been reported to affect the risk of treatment failure in some obese subjects. Some candidate genes for the prognosis of weight loss response related to energy expenditure are those codifying for the adrenergic receptors (ADBRs) and uncoupling proteins (UCPs), while genes related to appetite potentially affected by energy restriction are leptin (LEP), leptin receptor (LEPR), melanocortin pathways genes (MC3R, POMC) and the serotonin receptor. Furthermore, adipogenesis related genes such as peroxisome proliferator-activated receptor (PPAR gamma 2) and genes related to cytokines such as interleukin-6 (IL-6) and lipid metabolism including hepatic lipase (LIPC), perilipin (PLIN) and lipoprotein lipase (LPL) have also been associated to the weight lowering outcome induced by hypocaloric diets. Therefore, this review shows preliminary evidence from human studies that support the existence of a genetic component in the fat reduction process associated to a negative energy balance.
 ...
PMID:Genotype-dependent response to energy-restricted diets in obese subjects: towards personalized nutrition. 1829 17


1 2 3 4 Next >>