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

Studies employing nonselective serotonin 5-HT(2C) receptor agonists and antagonists have implicated this receptor subtype in many of the actions of serotonin. To further examine the function of this receptor, 5-HT(2C) receptor mutant mice were generated; studies of these animals reveal pleiotropic neurobehavioural effects of the mutation. Three examples are described: (1) Mutants exhibit chronically elevated food intake and the development of an obesity syndrome during the 'middle-age' portion of their lifespan. Their potential utility as a model of human obesity is further indicated by their enhanced sensitivity to high-fat feeding, leading to the development of type 2 diabetes. (2) 5-HT(2C) receptor mutants also display infrequent and sporadic spontaneous seizures. Further studies suggested the presence of globally enhanced neuronal network excitability in these mice. These findings raise the possibility that 5-HT(2C) receptors mediate a role for serotonin in the suppression of seizure activity. (3) Behavioural analysis of mutant mice revealed abnormal performance in a spatial learning task and altered exploratory behaviour, associated with perturbed long-term potentiation restricted to the dentate gyrus perforant path synapse. Taken together, the above findings implicate 5-HT(2C) receptors in the serotonergic regulation of feeding, neuronal network excitability, and hippocampal function.
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PMID:Knockout Corner: Neurobehavioural consequences of a serotonin 5-HT(2C) receptor gene mutation. 1128 72

We studied the effects of the novel noradrenaline and serotonin (5-HT) reuptake inhibitor sibutramine on feeding and body weight in a rat model of dietary obesity, and whether it interacts with hypothalamic neuropeptide Y (NPY) neurones. Chow-fed and dietary-obese (DIO) male Wistar rats were given sibutramine (3 mg kg(-1) day(-1) p.o.) or deionized water for 21 days. Sibutramine decreased food intake throughout the treatment period in both dietary-obese rats (P<0.0001) and lean rats (P<0.0001). Weight gain was reduced so that final body weight was 10% lower in dietary-obese (P<0.005) and 8% lower in lean (P<0.05) rats versus their untreated controls. Plasma leptin concentration was lower in sibutramine-treated dietary-obese rats (P<0.05), and in treated lean rats (P<0.05). Using the homeostasis model assessment (HOMA) as a measure of insulin resistance, untreated DIO rats were significantly more insulin resistant than controls (P<0.005), and this was corrected by sibutramine treatment (P<0.05). Neither hypothalamic NPY mRNA nor NPY peptide levels in a number of hypothalamic nuclei were significantly altered by sibutramine compared to untreated controls. The hypophagic and anti-obesity effects of sibutramine in dietary-obese Wistar rats appear not to be mediated by inhibition of ARC NPY neurones.
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PMID:Sibutramine reduces feeding, body fat and improves insulin resistance in dietary-obese male Wistar rats independently of hypothalamic neuropeptide Y. 1130 62

To elucidate the role of serotonin in the maintenance of normal breathing and upper airway (UA) patency in obesity, we studied the effects of systemic administration of ritanserin, a serotonin (5-HT) 2A and 2C receptor antagonist, on ventilation (V E) during room air breathing and during hypoxic (10% O2) and hypercapnic (4% CO2) ventilatory challenges in awake young (6-8 wk) and older (7-8 mo) obese and lean Zucker (Z) rats. Older obese Z rats adopted a more rapid shallow breathing pattern compared with older lean rats. The administration of ritanserin (1 mg/kg intraperitoneally) to older obese rats resulted in a reduction in V E (439 +/- 35 [SD] to 386 +/- 41 ml/kg/min, p < 0.01), a decrease in respiratory rate, a prolongation of inspiratory time, and an increase in V O2 (16.4 +/- 1.7 to 18.2 +/- 1.9 ml/kg(0.75)/min, p < 0.05) during room air breathing. By comparison, it had little effect on ventilation in young lean and obese Z or older lean Z rats. Ritanserin also had no effect on ventilatory responses to either hypoxia or hypercapnia in young or older lean and obese Z rats. The collapsibility of the isolated UA was examined in older Z rats. The pharyngeal critical pressure (Pcrit) of older obese rats was significantly greater than that of lean rats (p < 0.05), indicating that obese rats have more collapsible UA than lean rats. The administration of ritanserin significantly increased Pcrit in older obese rats (-1.6 +/- 0.3 to -0.8 +/- 0.2 cm H2O, p < 0.01) and in lean rats (-3.1 +/- 1.0 to -2.4 +/- 0.6 cm H2O, p < 0.05). We suggest that the 5-HT(2A/2C) receptor subtype plays an important role in the maintenance of UA stability and normal breathing in obesity, and we speculate that older obese Z rats may have augmented serotonergic control of UA dilator muscles as a mechanism to prevent pharyngeal collapse.
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PMID:Serotonergic modulation of ventilation and upper airway stability in obese Zucker rats. 1131 30

This article has attempted to point out some of the relationships between 5-HT and catecholamine (NE, DA) neurons in brain and the control of appetite and food intake. At least two bodies of evidence support this connection. The first is pharmacologic, and demonstrates that drugs that stimulate transmission across 5-HT and/or catecholamine synapses suppress hunger and food intake. The second is physiologic and metabolic, and reveals that the ingestion of foods, on either an acute (single meal) or chronic basis, can reliably modify the uptake of TRP and TYR into brain (and hypothalamus), and directly alter the synthesis of their transmitters (5-HT and the catecholamines, respectively). The synthesis of these two bodies of information has led to models by which (1) changes in dietary carbohydrate ingestion, by modifying brain TRP uptake and 5-HT production, may cause like changes in 5-HT release, and in the stimulation of 5-HT receptors in brain circuits that control carbohydrate appetite, and (2) dietary protein intake, by altering brain TYR uptake, directly influences DA and NE synthesis (notably in hypothalamus), perhaps providing a signal to brain circuits monitoring dietary protein adequacy regarding protein intake. In this case, one might imagine that stimulating DA and/or NE receptors in such circuits might suppress protein intake, a possibility we are now examining in rats. As indicated in the Introduction, the broader issue being touched upon in this article concerns the body's need to acquire and maintain an optimal (or adequate) nutritional balance (for growth and ultimately, reproductive success). Rats and humans evolved in an environment that does not provide continuous access to all essential nutrients, and one that presents nutrients in a complex matrix (other animals, plants) that can also include toxic compounds. Together with the fact that animals and humans do not carry a guidebook to healthy eating, we must presume that the brain mechanisms that have evolved to optimize the acquisition of essential nutrients are 'automatic' (i.e., not conscious) and quite complex. In this context, the relationships described here must be viewed as rudimentary, touching only a small portion of this complex regulatory mechanism. The hope is, as further insights develop, that we will gain a better understanding of the workings of these mechanisms, and also be able to apply this knowledge to the development of better pharmacologic (and other) aids for controlling appetite and obesity in our modern, man-made environment.
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PMID:Diet, monoamine neurotransmitters and appetite control. 1151 Apr 34

To clarify the neurochemical backing of aurothioglucose (ATG)-induced obesity in mice, we investigated lesion sites, hypothalamic neurotransmitters and c-Fos-like immunoreactivity (Fos-IR). At day 2 after ATG, tissue loss or cells death was observed in several parts of the ventral area of the ventromedial hypothalamic nucleus (VMH), and the dorsal area of arcuate nucleus and in the nucleus of the solitary tract (NTS). However, the greater part of the VMH was retained. Body weight began to increase in week 1. Hypothalamic serotonin (5-HT) and the metabolites were increased at day 2. The contents of acetylcholine, norepinephrine and dopamine in the hypothalamus showed no significant change. In week 1, the area shown tissue loss was compacted and plugged up. In the control group, most obvious c-Fos-like immunoreactive region was paraventricular nucleus (PVN). At day 2, Fos-IR was observed around destroyed regions in the hypothalamus and NTS, but few Fos-IR was found in the other regions including PVN. The Fos-IR around destroyed regions diminished after week 1. In week 3, Fos-IR in the PVN increased. These results suggest that the development of ATG-induced obesity cannot be attributed to solely VMH destruction. The restoration processes of the neuronal dysfunction involving PVN seem to play an important role in the development of obesity. NTS lesion and 5-HT system might contribute to decrease in food intake for several days after ATG.
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PMID:Development of obesity and neurochemical backing in aurothioglucose-treated mice. 1157 Jul

5-HT(1B) receptors have a regulatory role in serotonergic activity and influence feeding behavior and body weight. Because the absence of 5-HT(1B) receptors may cause changes in this regulation, body weight was measured in male and female 5-HT(1B) receptor knockout (5-HT(1B) KO) and wildtype (WT) mice from weaning until the age of 30 weeks. In both genders, 5-HT(1B) KO mice had a higher body weight than WT mice (17% and 9%, respectively). Body weight was significantly higher for males over the entire period and for females from Week 18 onwards. Absolute food and water consumption were related to body weight. However, relative to body weight, males consumed more than females. 5-HT(1B) KO males drank strikingly more water. Housing mice singly reduced food and water intake in males, but not in females. Plasma leptin levels and most organ weights did not differ between genotypes, indicating that higher body weight in 5-HT(1B) KO mice is not related to obesity. Relative to body weight, brains and adrenals were larger in females, while heart and liver were smaller. Kidneys were smaller in females, but larger in 5-HT(1B) KO mice, while lungs showed opposite effects. Spleen and testes were smaller in 5-HT(1B) KO mice. Although 5-HT(1B) KO males are more aggressive, testosterone levels were not different from WT mice. Basal corticosterone levels were similar in all groups and increased in response to mild stress, particularly in females. Lifelong absence of 5-HT(1B) receptors in mice resulted in clear phenotypic differences in body weights and food and water intake. Lacking this receptor increases body growth, without signs of obesity. A potential genetic background effect influencing this phenotype is discussed.
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PMID:Male and female 5-HT(1B) receptor knockout mice have higher body weights than wildtypes. 1179 Apr 10

When outbred Sprague--Dawley rats are placed on a diet relatively high in fat and calories (HE diet), half develop diet-induced obesity (DIO), while the rest are diet-resistant (DR). When fed a low fat chow diet from weaning, DIO- and DR-prone rats weigh the same, but DIO-prone rats have a number of abnormalities of neural function, many of which are normalized when they become obese after chronic exposure to a HE diet. Because of its important role in the regulation of energy homeostasis in the hypothalamus, we examined the ratio of serotonin (5-HT) to its metabolite, 5-hydroxyindolacetic acid (5HIAA), as an index of transmitter turnover in micropunches from various brain areas in these rats. While still on chow, both DIO- and DR-prone rats showed lower 5-HT turnover in most brain areas sampled during the last hour of the light phase, when animals become active and begin foraging for food, as compared to the first hour of the light phase, when animals are generally quiescent and not eating. However, unlike DR-prone rats, DIO-prone rats did not show a significant time-dependent difference in 5-HT turnover in either the arcuate or paraventricular hypothalamic nuclei. When fasted for 48 h, both DIO- and DR-prone rats showed a generalized 16--46% decrease in 5-HT turnover in the dorsomedial nucleus, perifornical lateral hypothalamus, dentate gyrus and motor cortex as compared to their free-fed counterparts. However, fasted DIO-prone rats showed a 53% greater reduction in the ventromedial nucleus turnover than fasted DR-prone rats. Finally, when DIO rats became obese after 14 weeks on the HE diet, their abnormalities in hypothalamic 5-HT turnover at the end of the light phase were normalized. Thus, DIO-prone rats show abnormalities of diurnal and fasting-induced alterations in brain 5-HT turnover which may predispose them to become obese when dietary fat and caloric density are increased. Once obesity develops, these abnormalities, like those of several other hypothalamic transmitters and peptides, are normalized. This may contribute to the persistence of obesity once it develops.
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PMID:Dysregulation of hypothalamic serotonin turnover in diet-induced obese rats. 1186 22

This review summarizes the neurochemical, therapeutic and adverse effects of serotonin (5-HT) releasing agents. The 5-HT releaser (plus minus)-fenfluramine is composed of two stereoisomers, (+)-fenfluramine and (minus sign)-fenfluramine, which are N-de-ethylated to yield the metabolites, (+)-norfenfluramine and (minus sign)-norfenfluramine. Fenfluramines and norfenfluramines are 5-HT transporter substrates and potent 5-HT releasers. Other 5-HT releasing agents include m-chlorophenylpiperazine (mCPP), a major metabolite of the antidepressant drug trazodone. Findings from in vitro and in vivo studies support the hypothesis that fenfluramines and mCPP release neuronal 5-HT via a non-exocytotic carrier-mediated exchange mechanism involving 5-HT transporters. (+)-Norfenfluramine is a potent 5-HT(2B) and 5-HT(2C) receptor agonist. The former activity may increase the risk of developing valvular heart disease (VHD), whereas the latter activity is implicated in the anorectic effect of systemic fenfluramine. Anorectic agents that increase the risk of developing primary pulmonary hypertension (PPH) share the common property of being 5-HT transporter substrates. However, these drugs vary considerably in their propensity to increase the risk of PPH. In this regard, neither trazodone nor mCPP is associated with PPH. Similarly, although some 5-HT substrates can deplete brain 5-HT (fenfluramine), others do not (mCPP). In addition to the established indication of obesity, 5-HT releasers may be helpful in treating psychiatric problems such as drug and alcohol dependence, depression and premenstrual syndrome. Viewed collectively, it seems possible to develop new medications that selectively release 5-HT without the adverse effects of PPH, VHD or neurotoxicity. Such agents may have utility in treating a variety of psychiatric disorders.
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PMID:Serotonin releasing agents. Neurochemical, therapeutic and adverse effects. 1188 73

Sibutramine offers three types of benefit in weight management: by enhancing weight loss, by improving weight maintenance and by reducing the comorbidities of obesity. The clinical effects of sibutramine are explained through its known mode of action as a serotonin (5-HT) and noradrenaline reuptake inhibitor (SNRI). This dual mechanism of action results in two synergistic physiological effects--a reduction in energy intake and an increase in energy expenditure, which combine to promote and maintain weight loss.
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PMID:How does sibutramine work? 1191 6

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.
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PMID:Increased abdominal obesity in subjects with a mutation in the 5-HT(2A) receptor gene promoter. 1207 91


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