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

Several drugs have been linked to valvulopathy in humans, including therapeutic agents for obesity, Parkinson's disease and migraine. There is increasing evidence that the 5-hydroxytryptamine 2B receptor (5HT2BR) activation and/or increased circulating 5HT (5-hydroxytryptamine) may play a significant role in the pathogenesis of drug-induced valvulopathy. In the present study, we investigated whether 7-day 5HT subcutaneous injections led to structural and compositional abnormalities in conjunction with transcriptomic modulation of 5HT2BR and 5HT transporter (5HTT) genes in the aortic and mitral valves of Sprague-Dawley (SD) rats. Subcutaneous injections of 5HT for 7 days resulted in thickening and compositional alteration of aortic and mitral valves in SD rats. More specifically, valve-leaflets from 5HT-treated rats had greater valve thickness, a higher amount of glycosaminoglycans (GAGs) and a lower amount of collagen. The compositional alteration was associated with up-regulation and down-regulation of 5HT2BR and 5HTT genes, respectively. The present study strongly suggests that the activation of 5HT2BR and inhibition of 5HTT played a significant role in the pathogenesis of 5HT-induced valvulopathy in SD rats. Thus, these findings further highlight the necessity and/or utilization of animal models to screen potential valvular effects of serotonergic compounds.
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PMID:5-hydroxytryptamine (5HT)-induced valvulopathy: compositional valvular alterations are associated with 5HT2B receptor and 5HT transporter transcript changes in Sprague-Dawley rats. 1851 Dec 49

The aim of our study was to investigate the direct effects of atypical antipsychotics on muscle cell functions in order to ascertain the diabetic liability of these drugs. We investigated the effects of olanzapine, clozapine and alpha-methyl-5-hydroxytryptamine on basal glucose uptake and glucose uptake in response to insulin using in vitro cultures of mouse skeletal muscle satellite cells (C2C12). We extended our study to the effects of these compounds on cell proliferation, survival and differentiation into myotubes and on the growth of differentiated myotubes. Olanzapine and alpha-methyl-5-HT stimulated 2-deoxyglucose uptake in C2C12 myoblasts in a dose-dependent manner (minimal effective dose: 2 microM olanzapine and 10 microM alpha-methyl-5-HT). The treatment with clozapine had no effect on glucose transport. Insulin and olanzapine increased the plasma membrane (PM) abundance of glucose transporter GLUT4. We investigated whether protein kinase Akt (PKB) and AMP-dependent kinase may participate in mediating olanzapine effects on glucose transport. Clozapine and olanzapine did not induce DNA laddering in differentiating myoblasts and differentiated myotubes and did not affect myotube growth. Olanzapine-induced glucose disposal in vitro is consistent with the acute lowering of plasma glucose/insulin concentrations that occurs in rats before olanzapine-induced overeating [Albaugh, V.L., Henry, C.R., Bello, N.T., Hajnal, A., Lynch, S.L., Halle, B., Lynch, C.J., 2006. Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents. Obesity 14, 36-50].
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PMID:Effects of olanzapine on glucose transport, proliferation and survival in C2C12 myoblasts. 1851 90

We investigated the feeding behavior of mice carrying a non-functional 5-hydroxytryptamine-6 receptor (5-HT6). Homozygous mutant mice on C57BL/6 background were grossly normal and showed normal growth when fed a low-fat chow diet. When fed a high-fat diet, the mutant mice consumed approximately 8% less food while gaining approximately 35% less weight over an 11-week study period than did the wild-type controls. Body composition analysis of mice on high-fat feeding showed that the reduced weight gain in the mutant mice was mostly due to reduced fat accumulation. Given the documented role of the serotonin systems in human feeding, our results provide an interesting piece of evidence supporting the development of 5-HT6 receptor antagonists for treating obesity.
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PMID:Reduced sensitivity to diet-induced obesity in mice carrying a mutant 5-HT6 receptor. 1875 68

We have previously shown that adult female rats exposed to intra-uterine malnutrition were normophagic, although obese and resistant to insulin-induced hypophagia. The present study aimed at examining aspects of another important catabolic component of energy homeostasis control, the hypothalamic serotonergic function, which inhibits feeding and stimulates energy expenditure. Pregnant dams were fed ad libitum or were restricted to 50 % of ad libitum intake during the first 2 weeks of pregnancy. Control and restricted 4-month-old progeny were studied. The restricted rats had increased body adiposity with normal daily food intake but failed to respond with hypophagia to an intracerebroventricular injection of serotonin (5-hydroxytryptamine; 5-HT). Stimulation, by food ingestion, of extracellular levels of serotonin in medial hypothalamus microdialysates was more pronounced and lasted longer in the restricted than in the control rats. In the restricted group, hypothalamic levels of 5-HT 2C receptor protein tended to be reduced (P = 0.07) while the levels of 5-HT1B receptor and serotonin transporter proteins were significantly elevated (36 and 79 %, respectively). In conclusion, female rats undernourished in utero had normophagic obesity as adults but had an absence of serotonin-induced hypophagia and low hypothalamic levels of the 5-HT 2C receptor. Compensatory adaptations for the functional serotonergic impairment were evidenced, such as an enhanced release of serotonin in response to a meal allied to up-regulated hypothalamic 5-HT1B and transporter expression. Whether these compensations will persist in later life warrants further investigation. Moreover, it cannot be ruled out that the serotonergic component of energy expenditure was already impaired, thus contributing to the observed body-fat phenotype.
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PMID:Impairment of the serotonergic control of feeding in adult female rats exposed to intra-uterine malnutrition. 1878 79

The present study concerns the effectiveness of a selective 5-hydroxytryptamine (5-HT)-1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in long term sugar diet treated rats. Male albino wistar rats were divided into control and test groups. Test animals were given sugar (5 g/10 ml water) orally for three weeks. Food intakes and body weight of all rats were measured weekly. After three weeks control and test animals were further divided into two groups i.e. saline injected and drug injected. 8-OH-DPAT at a dose of 0.25mg/Kg was injected to a group of normal diet treated and another group of sugar diet treated rats. Other two groups were injected with saline. 5-HT syndrome and food intakes at 2h and 4h were monitored. Then animals were decapitated to collect brain samples for the estimation of 5-HT and 5-hydroxyindole acetic acid (5-HIAA) levels by HPLC-EC method. We observed that weekly cumulative food intakes increased and body weights decreased in sugar diet treated rats. 8-OH-DPAT produced hyperactivity syndrome in both control and sugar treated rats. But these values were smaller in sugar diet than normal diet treated rats. Hyperphagic effects of 8-OH-DPAT were greater in normal diet than sugar diet treated rats. 5-HT and 5-HIAA levels were not altered. The results suggesting a desensitization of pre as well as postsynaptic 5-HT-1A receptors in rats treated with sugar diet are discussed in the context of a role of sugar diet in the precipitation of obesity and other neuropsychiatric illnesses.
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PMID:Desensitization of pre and post synaptic 5-HT-1A receptor responses following long term consumption of sugar rich diet: implications for sugar-induced obesity. 1893 Aug 50

The attenuation of food intake as induced by an increase in serotonergic (5-hydroxytryptamine, 5-HT) efficacy has been a target of antiobesity pharmacotherapies. However, the induction of tolerance and/or side-effects limited the clinical utility of the earliest serotonin-related medications. With the global prevalence of obesity rising, there has been renewed interest in the manipulation of the serotonergic system as a point of pharmacological intervention. The serotonin(2C) receptor (5-HT(2C)R), serotonin(1B) (rodent)/serotonin(1Dbeta) (human) receptor (5-HT(1B/1Dbeta)R) and serotonin(6) receptor (5-HT(6)R) represent the most promising serotonin receptor therapeutic targets. Canonical serotonin receptor compounds have given way to a myriad of novel receptor-selective ligands, many of which have observable anorectic effects. Here we review serotonergic compounds reducing ingestive behaviour and discuss their clinical potential for the treatment of obesity.
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PMID:Pharmacological targeting of the serotonergic system for the treatment of obesity. 1902 84

Drugs activating 5-hydroxytryptamine 2C receptors (5-HT2CRs) potently suppress appetite, but the underlying mechanisms for these effects are not fully understood. To tackle this issue, we generated mice with global 5-HT2CR deficiency (2C null) and mice with 5-HT2CRs re-expression only in pro-opiomelanocortin (POMC) neurons (2C/POMC mice). We show that 2C null mice predictably developed hyperphagia, hyperactivity, and obesity and showed attenuated responses to anorexigenic 5-HT drugs. Remarkably, all these deficiencies were normalized in 2C/POMC mice. These results demonstrate that 5-HT2CR expression solely in POMC neurons is sufficient to mediate effects of serotoninergic compounds on food intake. The findings also highlight the physiological relevance of the 5-HT2CR-melanocortin circuitry in the long-term regulation of energy balance.
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PMID:5-HT2CRs expressed by pro-opiomelanocortin neurons regulate energy homeostasis. 1903 16

The noradrenaline (NA) and serotonin reuptake inhibitor, sibutramine, gives effective weight loss, but full efficacy cannot be attained at approved doses due to cardiovascular side effects. We assessed in rats the contributions of NA and serotonin transporters to sibutramine's hypophagic and cardiovascular effects, and whether selective 5-hydroxytryptamine (5-HT(1A)) receptor activation could counteract the latter without affecting the former. Food intake was assessed in freely feeding rats and cardiovascular parameters in conscious telemetered rats. Ex vivo radioligand binding was used to estimate brain monoamine transporter occupancy. Sibutramine (1-10 mg/kg p.o.) dose-dependently reduced food intake; however, 10 mg/kg p.o. markedly elevated blood pressure and heart rate. Sibutramine gave greater occupancy of NA than serotonin reuptake sites. Coadministration of the selective 5-HT(1A) agonist F-11440 (2.5 mg/kg p.o.) attenuated sibutramine-induced hypertension and tachycardia without altering its food intake effects. The selective NA reuptake inhibitors, nisoxetine or reboxetine, did not alter food intake alone, but each reduced food intake when combined with F-11440. These results suggest that sibutramine-induced hypophagic and cardiovascular effects are largely due to increased brain synaptic NA via NA reuptake inhibition, and that 5-HT(1A) activation can counter the undesirable cardiovascular effects resulting from increased sympathetic activity. Selective NA reuptake inhibitors did not reduce food intake alone but did when combined with 5-HT(1A) activation. Hence increased synaptic serotonin, via serotonin reuptake inhibition or 5-HT(1A) activation, together with increased NA, would appear to produce hypophagia. Thus weight loss with minimal cardiovascular risk could be achieved by 5-HT(1A) activation combined with NA transporter blockade.
Obesity (Silver Spring) 2009 Mar
PMID:5-HT(1A) activation counteracts cardiovascular but not hypophagic effects of sibutramine in rats. 1921 64

Serotonin (5-hydroxytryptamine, 5-HT) participates in several functions of the gastrointestinal tract. Receptors in seven families (5-HT(1)-5-HT(7)) were identified, many of which are present on enterocytes, intrinsic and extrinsic neurons, interstitial cells, and gut myocytes. Most 5-HT is released from enterochromaffin cells in response to physiologic and pathologic stimuli. Roles of 5-HT in health include control of normal gut motor activity, secretion, and sensation, and regulation of food intake and cell growth. Abnormalities of serotonergic function contribute to symptom genesis in functional bowel disorders, inflammatory and infectious diseases of the gut, emetic responses to varied stimuli, obesity, and dysregulation of cell growth. Therapies acting as agonists or antagonists of 5-HT receptors or that modulate 5-HT reuptake play prominent roles in managing these conditions, although use of many agents is hampered by cardiopulmonary complications. Novel agents are in testing, which may exhibit efficacy without significant toxicity.
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PMID:Serotonin and the GI tract. 1976 66

Obesity is a major public health problem. For many obese patients, diet and exercise are an inadequate treatment and bariatric surgery may be too extreme of a treatment. As with many other chronic diseases, pharmacologic treatment may be an attractive option for selected obese patients. Antiobesity drugs may potentially work through one of three mechanisms: (1) appetite suppression, (2) interference with absorption of nutrients, and (3) increased metabolism of nutrients. The three most widely prescribed drugs approved to treat obesity are phentermine, sibutramine, and orlistat. Drugs approved for treating obesity usually result in an additional weight loss of approximately 2-5 kg in addition to placebo. For pharmacologic therapy in obesity to be widely utilized, greater effectiveness and safety will be needed. Four types of single-agent drugs are in late stage development, including (1) selective central cannabinoid-1 receptor blockers, (2) selective central 5-hydroxytryptamine 2C serotonin receptor agonists, (3) an intestinal lipase blocker, and (4) central-acting incretin mimetic drugs. Four combination agent compounds in late stage development include (1) Contrave, which combines long-acting versions of naltrexone and bupropion; (2) Empatic, which combines long-acting bupropion and long-acting zonisamide; (3) Qnexa, which combines phentermine with controlled release topiramate; and (4) an injectable combination of leptin and pramlintide. Peptide YY and melanin-concentrating hormone receptor-1 antagonists are centrally acting agents in early stage development. It is expected that several new drug products for obesity will become available over the next few years. Their role in managing this disease remains to be determined.
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PMID:Drugs in the pipeline for the obesity market. 1988 78


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