Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fenfluramine is an amphetamine analogue which has been widely used in the treatment of obesity. In rodents, non-human primates, and humans, fenfluramine is associated with some indices of neurotoxicity, as well as pulmonary hypertension and cardiac valve pathology. In the present study, d-fenfluramine was found to be cytotoxic to the serotonin (5-HT) transporter (5-HTT) expressing human placental choriocarcinoma cells. d-Fenfluramine caused DNA fragmentation and apoptosis. Apoptosis was not observed after the 5-HTT had been blocked by fluoxetine, indicating that intact 5-HTT function is required for d-fenfluramine to induce programmed cell death. These observations in a human cell line may reflect a possible mechanism associated with the risks of fenfluramine administration in several species, including humans.
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PMID:The appetite suppressant d-fenfluramine induces apoptosis in human serotonergic cells. 980 3

Sibutramine is an orally administered centrally acting weight management agent apparently devoid of amphetamine-like abuse potential. Its primary (M2; BTS 54,505) and secondary (M1; BTS 54,354) amine metabolites are pharmacologically active and are thought to induce the natural processes leading to enhancement of satiety and thermogenesis by inhibiting serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline (norepinephrine) reuptake. In clinical trials, once-daily sibutramine was administered at dosages of < or = 30 mg for < or = 24 weeks and 10 or 15 mg for 1 year in conjunction with reduced calorie intake, increased daily exercise and advice on eating behaviour. Dose-related bodyweight loss was greater with sibutramine than with placebo. Clinical effects were most commonly apparent at dosages > or = 10 mg/day. Weight loss of > 1% within the first month of treatment appears indicative of good long term response with sibutramine. Weight loss was maintained during therapy for 1 year; longer term data are lacking. Weight regain occurred after treatment cessation in studies of < or = 24 weeks' duration; data from longer trials are unavailable. Up to 15% of patients in < or = 6-month studies did not respond to treatment irrespective of dose. Obese patients with type 2 (non-insulin-dependent) diabetes or hypertension lost significantly more mean bodyweight with sibutramine than with placebo, although weight loss was less than that in obese patients without comorbidities. The effect of sibutramine on mean fasting blood glucose levels and plasma lipid levels was unclear. Sibutramine, compared with placebo, statistically significantly increased blood pressure and heart rate in obese patients with or without hypertension when given for up to 12 months. However, after 12 weeks' treatment in hypertensive obese patients, diastolic blood pressure was reduced by similar amounts with sibutramine or placebo. Concerns over potential pressor effects with sibutramine are reflected in the manufacturer's dosage and administration recommendations.
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PMID:Sibutramine. A review of its contribution to the management of obesity. 987 96

Serotonin 5-HT2C receptor null mutant mice were generated to assess the contribution of this receptor to the actions of serotonin. Mutant mice displayed both an epilepsy and obesity phenotype. The epilepsy syndrome was characterized by spontaneous seizures, lowered seizure threshold, enhanced seizure propagation and sound-induced seizure susceptibility. These findings implicate 5-HT2C receptors in the regulation of neuronal network excitability. It was also observed that body weight and adipose tissue deposition were elevated in adult mutant mice relative to their wild type littermates. Paired-feeding studies suggest that the obesity syndrome is a result of increased food intake. In addition, mutants displayed reduced sensitivity to the appetite suppressant actions of non-specific serotonergic agonists. These studies establish a role for 5-HT2C receptors in the serotonergic regulation of body weight and food intake.
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PMID:Epilepsy and obesity in serotonin 5-HT2C receptor mutant mice. 992 41

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

Obesity usually results from unwanted variations in metabolism. Inadequate neurotransmission, thermogenesis, or acylation underlie about 90% of cases. These are complex, weakly heritable, polygenic traits. Mutations in major gene loci cause another 5% of cases, and still another 5% of cases are due to gluttony. Careful observation can help define the type of obesity. All forms are associated with excess mortality and require lifelong episodic or continuous management. Management centers around diet, exercise, behavior therapy, and life-style counseling. Serotonin agonists and serotonin uptake inhibitors, as well as alternative therapies like phototherapy and 5-hydroxytryptophan are worthwhile for neurotransmitter inadequacy, except in children and pregnant women. When thermogenesis is inadequate, intake may be normal and weight reduction may require subnormal intake. Some degree of obesity may be required for optimal health in patients with inadequate acylation. In some Mendelian syndromes, obesity may balance a metabolic error, and weight reduction may restore metabolic imbalance.
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PMID:How can genetics help in the management of obesity? 1066 13

Medical and social pressures have led to increased emphasis on dieting. However, there has been a concurrent world wide increase of obesity. Therefore, much attention has been paid to the development of drugs which decrease appetite. The most extensively used drug of this type over the past three decades has been the serotonergic compound fenfluramine. Recent findings have cast doubt on the previously accepted view that its action requires the release of central 5-HT. Instead, it seems likely that action on specific 5-HT receptors independently of 5-HT stores is involved. It is ironic that these new developments in understanding its mechanism of action have coincided with the recognition of its cardiovascular side-effect apparent especially in patients treated with d-fenfluramine combined with phentermine. This has forced the withdrawal of fenfluramine (both as racemate and d-isomer) from clinical use. The implications of these developments are commented upon.
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PMID:The serotonergic appetite suppressant fenfluramine. Reappraisal and rejection. 1072 Oct 44

Combined administration of the amphetamine analogs phentermine and fenfluramine (PHEN/FEN) has been used in the treatment of obesity. While these medications are thought to modulate monoamine transmission, the precise neurochemical effects of the PHEN/FEN mixture have not been extensively studied. To assess the mechanism of PHEN/FEN action, in vivo microdialysis studies were performed in the nucleus accumbens of conscious freely moving rats. A series of amphetamine derivatives including phentermine, chlorphentermine, fenfluramine, and PHEN/FEN (1:1 ratio), were infused locally into the accumbens via reverse-dialysis (1, 10, 100 microM) or injected systemically (1 mg/kg, ip). Dialysate samples were assayed for dopamine (DA) and serotonin (5-HT) by high-performance liquid chromatography with electrochemical detection. When infused locally, phentermine preferentially increased extracellular DA, whereas fenfluramine selectively increased extracellular 5-HT. Local administration of chlorphentermine or the PHEN/FEN mixture caused parallel elevations of both transmitters. Analogous results were obtained when the drugs were injected systemically. Phentermine stimulated robust locomotor activity in mice, whereas chlorphentermine and fenfluramine did not. PHEN/FEN caused modest locomotor stimulation after a low dose, but had no effect at the highest dose. Accumulating evidence suggests that chronic drug and alcohol abuse is associated with deficits in both DA and 5-HT neuronal function. Thus, dual activation of DA and 5-HT neurotransmission with monoamine releasing agents may be an effective treatment strategy for substance use disorders, as well as for obesity. Synapse 36:102-113, 2000. Published 2000 Wiley-Liss, Inc.
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PMID:Effects of phentermine and fenfluramine on extracellular dopamine and serotonin in rat nucleus accumbens: therapeutic implications. 1076 57

Despite a rising worldwide epidemic of obesity there is currently only a very small number of anti-obesity drugs available to manage the problem. Large numbers of differing pharmacological agents reliably produce a reduction in food intake when administered acutely to animals, and when administered chronically they result in a significant decrease in body mass. Behavioural analysis of drug-induced anorexia in animals demonstrates that various compounds profoundly effect feeding behaviour in differing ways. This indicates the variety of mechanisms by which pharmacological agents can induce changes in food intake, body weight and eventually body composition. Some of the same drugs produce decreases in food intake and weight loss in humans. Some of these drugs do so by modifying the functioning of the appetite system as measured by subjective changes in feelings of hunger and fullness (indices of satiety). Such drugs can be considered as "appetite suppressants" with clinical potential as anti-obesity agents. Other drugs induce changes in food intake and body weight through various physiological mechanisms inducing feelings of nausea or even by side effect related malaise. Of the drugs considered suitable candidates for appetite suppressants are agents which act via peripherally satiety peptide systems (such as CCK, Bombesin/GRP, Enterostatin and GLP-1), or alter the CNS levels of various hypothalamic neuropeptides (NPY, Galanin, Orexin and Melanocortins) or levels of the key CNS appetite monoamine neurotransmitters such as serotonin (5-HT) and noradrenaline (NA). Recently, the hormone leptin has been regarded as a hormonal signal linking adipose tissue status with a number of key central nervous system circuits. The peptide itself stimulates leptin receptors and it links with POMC and MC-4 receptors. These receptors may also provide drug targets for the control of appetite. Any changes induced by a potential appetite suppressant should be considered in terms of the (i) psychological experience and behavioural expression of appetite, (ii) metabolism and peripheral physiology, and (iii) functioning of CNS neural pathways. In humans, modulation of appetite may involve changes in total caloric consumption, subjective changes in feelings of hunger and fullness, preferences for specific food items, and general macronutrient preferences. These may be expressed behaviourally as changes in meal patterns, snacking behaviour and food choice. Within the next 20 years it is certain that clinicians will have a new range of anti-obesity compounds available to choose from. Such novel compounds may act on a single component of the appetite system or target a combination of these components detailed in this review. Such compounds used in combination with lifestyle changes and dietary intervention may be useful in dealing with the rising world epidemic of obesity.
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PMID:Pharmacology of appetite suppression. 1085 85

Study of neurotransmitter role in food intake regulation in a leptin signaling deficient model, such as the Zucker rat, would benefit in the understanding of mechanisms of human obesity, in which leptin resistance is a common syndrome. We studied dopamine (DA) and serotonin (5-HT) concentrations in vivo in the ventromedial nucleus (VMN) of the hypothalamus, as they relate to eating after food deprivation in obese and lean 9-week-old male Zucker rats. DA and 5-HT concentrations were measured by HPLC via microdialysis before and during refeeding in 24-h food-deprived rats. Before food was provided, mean baseline DA and 5-HT levels were lower in obese than in lean rats (9.2 +/- 0.9 vs 15.1 +/- 1.9 pg/10 microl, p < 0.01, and 0.68 +/- 0.05 vs 1.17 +/- 0.02 pg/10 microl, p < 0.001, respectively). Food intake was accompanied by a decrease in DA levels in both obese and lean rats to 64% (p < 0.01) and 65% (p < 0.02) of their baseline levels respectively. 5-HT levels were significantly increased during eating by 41% in obese and 35% in lean rats (p < 0.01) from the baseline levels. Thus in obese rats with altered leptin signaling we found an unaltered pattern of DA and 5-HT release associated with food deprivation and refeeding, but with presence of their low levels. This points to an impaired postsynaptic monoaminergic action to produce an adequate metabolic response in obese Zucker rats in response to feeding state.
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PMID:Dopamine and serotonin VMN release is related to feeding status in obese and lean Zucker rats. 1092 45

When the hypothalamic ventromedial nucleus and arcuate nucleus were destroyed in rats by treatment with monosodium glutamate in the neonatal stage, increase in the Lee index (body weight 1/3/body length) and in retroperitoneal fat as well as decreases in spontaneous motor activity, food consumption and growth hormone secretion function associated with hypothalamic low body length obesity (monosodium glutamate-treated obesity; MSG-OB) were observed as these rats grew. Treatment with sibutramine at 3 and 10 mg/kg p.o. once a day continuously for 14 days improved these parameters, and the degree of improvement was dose related. The plasma lipid values in MSG-OB rats, which were the same as those in normal rats, were decreased by consecutive administration of sibutramine. Levels of hypothalamic monoamines (MAs) such as norepinephrine, 5-HT (serotonin) and dopamine and their metabolites DOPAC, HVA and 5-HIAA were decreased in MSG-OB rats, and further decrease in them, though slight, was observed with consecutive daily administration of sibutramine, probably as a result of the feedback attributable to an increase in MA in synapses caused by inhibition of MA uptake by sibutramine. These results suggest that sibutramine can activate the MA nervous system by MA uptake inhibition in regions of the brain such as the lateral hypothalamic area and the paraventricular nucleus, which control food intake and sympathetic nerve activity, and the nigrostriatal area related to the extrapyramidal motor system, and thereby exhibit anti-obesity effects in the MSG-OB rat.
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PMID:Effects of chronic administration of sibutramine on body weight, food intake and motor activity in neonatally monosodium glutamate-treated obese female rats: relationship of antiobesity effect with monoamines. 1110 49


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