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

The importance of the central monoamines NE, DA and 5-HT in ingestive behavior has inevitably resulted in considerable effort being expended in attempting to implicate these monoamines in the mechanism of action of anorectic drugs. The statements that amphetamine-induced anorexia is unlikely to be due to central serotoninergic systems and that central noradrenergic and dopaminergic systems are not implicated in the appetite suppressant effect of fenfluramine are in all probability correct. However, to attribute the ability of drugs to decrease food intake unequivocally to a specific effect on central monoaminergic systems is almost certainly an oversimplification, due to the fact that other putative neurotransmitters, such as GABA and peptides, play a critical role in eating. This can be achieved either directly or by modulating the release of other transmitters. An added complication in attempting to correlate a specific neurochemical process to a behavioral effect, such as anorexia, is the complexity of the central actions of the drug. At best, a predominant but not an exclusive process can be identified. Perhaps the in-built constraint of attempting to correlate a specific neurochemical effect to the desired action of a drug is accountable for the absence of a second generation of centrally acting anorectic drugs. Dramatic progress has been made in elucidating the factors involved in ingestive behavior over the last 5-10 years. This information should, and must, provide the catalyst for more efficacious anorectic drugs because obesity represents one of the few major diseases for which adequate drug therapy does not exist.
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PMID:Neuropharmacology of drugs affecting food intake. 288 62

Neuropeptide Y (NPY), a 36 amino acid neuromodulator that is secreted by neurons throughout the peripheral and central nervous system, has been implicated in the control of many physiological processes. We have begun to examine its role in regulation of appetite, behavior, and excitotoxicity by examining mice that are unable to produce NPY as a consequence of gene inactivation. These mutant mice are remarkably normal when reared under standard vivarium conditions. Despite considerable evidence that NPY plays a central role in stimulating appetite, NPY-deficient mice eat normally, grow normally, and refeed after a fast normally. Furthermore, all of their endocrine responses to fasting are normal. The response of NPY-null mice to diet-induced obesity, chemically induced obesity (monosodium glutamate and gold thioglucose), and genetic-based obesity (lethal yellow agouti, Ay; uncoupling protein-diphtheria toxin transgenics, UCP-DT) were all normal. However, NPY deficiency does partially ameliorate the obesity and all of the adverse endocrine effects of leptin deficiency in ob/ob mice. NPY-null mice as well as mice deficient in both NPY and leptin are more sensitive to leptin, suggesting that NPY may normally have a tonic inhibitory action on leptin-mediated satiety signals. NPY-null mice display the normal voracious feeding response to injected NPY. Thus, the only condition where we have observed a role for NPY in body-weight regulation is in the context of complete leptin deficiency--where absence of NPY is beneficial. The activity and general behavior of NPY-null mice are normal. They appear to have normal spatial and contextual learning ability; however, they manifest more anxiety under some conditions. NPY-null mice occasionally display spontaneous, seizure-like events. They also are less able to terminate seizures induced by GABA receptor antagonists or glutamate receptor agonists. These observations are consistent with previous data suggesting that NPY plays an important role in dampening excitotoxicity.
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PMID:Life without neuropeptide Y. 976 8

The dopaminergic and opioidergic reward pathways of the brain are critical for survival since they provide the pleasure drives for eating, love and reproduction; these are called 'natural rewards' and involve the release of dopamine in the nucleus accumbens and frontal lobes. However, the same release of dopamine and production of sensations of pleasure can be produced by 'unnatural rewards' such as alcohol, cocaine, methamphetamine, heroin, nicotine, marijuana, and other drugs, and by compulsive activities such as gambling, eating, and sex, and by risk taking behaviors. Since only a minority of individuals become addicted to these compounds or behaviors, it is reasonable to ask what factors distinguish those who do become addicted from those who do not. It has usually been assumed that these behaviors are entirely voluntary and that environmental factors play the major role; however, since all of these behaviors have a significant genetic component, the presence of one or more variant genes presumably act as risk factors for these behaviors. Since the primary neurotransmitter of the reward pathway is dopamine, genes for dopamine synthesis, degradation, receptors, and transporters are reasonable candidates. However, serotonin, norepinephrine, GABA, opioid, and cannabinoid neurons all modify dopamine metabolism and dopamine neurons. We have proposed that defects in various combinations of the genes for these neurotransmitters result in a Reward Deficiency Syndrome (RDS) and that such individuals are at risk for abuse of the unnatural rewards. Because of its importance, the gene for the [figure: see text] dopamine D2 receptor was a major candidate gene. Studies in the past decade have shown that in various subject groups the Taq I A1 allele of the DRD2 gene is associated with alcoholism, drug abuse, smoking, obesity, compulsive gambling, and several personality traits. A range of other dopamine, opioid, cannabinoid, norepinephrine, and related genes have since been added to the list. Like other behavioral disorders, these are polygenically inherited and each gene accounts for only a small per cent of the variance. Techniques such as the Multivariate Analysis of Associations, which simultaneously examine the contribution of multiple genes, hold promise for understanding the genetic make up of polygenic disorders.
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PMID:Reward deficiency syndrome: genetic aspects of behavioral disorders. 1110 55

Obesity is often associated with a reduced ventilatory response and a decreased maximal exercise capacity. GABA is a major inhibitory neurotransmitter in the mammalian central nervous system. Altered GABAergic mechanisms have been detected in obese Zucker rats and implicated in their hyperphagic response. Whether altered GABAergic mechanisms also contribute to regulate ventilation and influence exercise capacity in obese Zucker rats is unknown and formed the basis of the present study. Eight lean [317 +/- 18 (SD) g] and eight obese (450 +/- 27 g) Zucker rats were studied at 12 wk of age. Ventilation at rest and ventilation during hypoxic (10% O(2)) and hypercapnic (4% CO(2)) challenges were measured by the barometric method. Peak O(2) consumption (VO(2 peak)) in response to a progressive treadmill test to exhaustion was measured in a metabolic treadmill. Ventilation and VO(2 peak) were assessed after administration of equal volumes of DMSO (vehicle) and the GABA(A) receptor antagonist bicuculline (1 mg/kg). In lean animals, bicuculline administration had no effect on ventilation and VO(2 peak). In obese rats, bicuculline administration significantly (P < 0.05) increased resting ventilation (465 +/- 53 and 542 +/- 72 ml. kg(-1). min(-1) for control and bicuculline, respectively), ventilation during exposure to hypoxia (899 +/- 148 and 1,038 +/- 83 ml. kg(-1). min(-1) for control and bicuculline, respectively), and VO(2 peak) (62 +/- 3.7 and 67 +/- 3.5 ml. kg(-0.75). min(-1) for control and bicuculline, respectively). However, in obese Zucker rats, ventilation in response to hypercapnia did not change after bicuculline administration (608 +/- 96 vs. 580 +/- 69 ml. kg(-1). min(-1)). Our findings indicate that endogenous GABA depresses ventilation and limits exercise performance in obese Zucker rats.
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PMID:GABAergic modulation of ventilation and peak oxygen consumption in obese Zucker rats. 1129 59

The administration of leptin to leptin-deficient humans, and the analogous Lepob/Lepob mice, effectively reduces hyperphagia and obesity. But common obesity is associated with elevated leptin, which suggests that obese humans are resistant to this adipocyte hormone. In addition to regulating long-term energy balance, leptin also rapidly affects neuronal activity. Proopiomelanocortin (POMC) and neuropeptide-Y types of neurons in the arcuate nucleus of the hypothalamus are both principal sites of leptin receptor expression and the source of potent neuropeptide modulators, melanocortins and neuropeptide Y, which exert opposing effects on feeding and metabolism. These neurons are therefore ideal for characterizing leptin action and the mechanism of leptin resistance; however, their diffuse distribution makes them difficult to study. Here we report electrophysiological recordings on POMC neurons, which we identified by targeted expression of green fluorescent protein in transgenic mice. Leptin increases the frequency of action potentials in the anorexigenic POMC neurons by two mechanisms: depolarization through a nonspecific cation channel; and reduced inhibition by local orexigenic neuropeptide-Y/GABA (gamma-aminobutyric acid) neurons. Furthermore, we show that melanocortin peptides have an autoinhibitory effect on this circuit. On the basis of our results, we propose an integrated model of leptin action and neuronal architecture in the arcuate nucleus of the hypothalamus.
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PMID:Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. 1137 81

Betel nut (Areca catechu) is chewed regularly by at least 10% of the world population, imported by immigrant users wherever they settle, and is the fourth most widely used addictive substance. It is thought, by users, to soothe the digestion and to be a stimulant and its use has a major role in social situations. Specific arecal alkaloids act as competitive inhibitors of GABA receptors and have widespread effects in the body, including actions on the brain, cardiovascular system, lungs, gut and pancreas. Nitrosated derivatives of arecal alkaloids, proven carcinogens inducing tumours throughout the upper gut and foregut derivatives in animals, are also associated with increased tumour risks in man. These nitrosated compounds are also diabetogenic in CD1 mice, producing a type 2 diabetes with obesity. Increased central obesity is found in association with betel usage in man as well as increases in circulating markers of inflammatory and cardiovascular damage. The effects of chronic betel usage in man are at least as diverse as those of smoking and the habit increases the risks of ill health.
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PMID:Metabolic effects of the consumption of Areca catechu. 1190 Jun 29

In the present study, we examined the potential impact of a T-to-C substitution at nucleotide 1519 of the GABA(A)alpha6 receptor subunit gene (GABRA6) on obesity and obesity-related phenotypes as well as circulating hormones, including salivary cortisol, in 284 unrelated Swedish men born in 1944. The subjects were genotyped by using PCR amplification followed by digestion with the restriction enzyme AlwNI. The frequency of allele T was 0.54 and that of allele C was 0.46. Carriers for the T allele (n = 211) had higher waist-to-hip ratio (p = 0.094) and abdominal sagittal diameter (p = 0.084) compared to homozygotes for the C allele (n = 56). The homozygotes for the T allele had, in comparison to heterozygotes, significantly (p = 0.004-0.024) higher mean cortisol levels at 11:45 am; at 30, 45, and 60 min after a standardized lunch; and finally at 5:00 pm. In addition, T/T subjects had significantly (p = 0.031) higher diurnal cortisol secretion compared to T/C subjects. Leptin, insulin, and glucose were not different across the genotype groups. In conclusion, these findings suggest a role of the point substitution (T-to-C) at nucleotide 1519 of GABRA6 in the predisposition to hypercortisolism and perhaps abdominal obesity. The pathophysiology may involve various environmental factors, particularly stress, that destabilize the GABA-hypothalamic-pituitary-adrenal systems in those with genetic vulnerability.
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PMID:Association between a variant at the GABA(A)alpha6 receptor subunit gene, abdominal obesity, and cortisol secretion. 1207 90

The exact mechanisms by which NO mediates its neuromodulatory effects within the central control of cardiovascular functions are still unclear. Both excitatory and inhibitory actions of NO in different regions of the brainstem have been reported, and that it could be caused by direct actions of NO on neurones and/or by NO-mediated changes in local cerebral blood flow. Microinjection studies suggest that direct modulation of neuronal activity by NO through cyclic 3'-5' guanosine monophosphate (cGMP)-dependent mechanisms predominates. In contrast, endogenous NO produces. only minor changes in local cerebral blood flow, and potentiation of NO-dependent vasodilation with an inhibitor of phosphodiesterase V (PDE5i) has no significant effect on sympathetic activity. Activation of the NO-system in the lower brain stem modulates various central and reflex-activated neuronal pathways. To a large extent, this appears to be mediated by NO-induced GABA- and glutamate-release within the ventrolateral medulla (VLM) and the nucleus of the solitary tract (NTS). In addition, NO has been shown to reduce local generation of angiotensin II (AII) in all areas. Recent studies suggest that the NO-mediated modulation of autonomic function is severely impaired in cardiovascular diseases. Possibly in conjunction with AII, which triggers and promotes superoxide radical generation, chronic oxidative stress (COS) could act as a key mediator of this process. Evidence supporting this hypothesis comes from studies on pigs that were chronically treated with organic nitrates to pharmacologically induce COS. In these animals, microinjection of superoxide dismutase into the rostral VLM (RVLM) diminished sympathetic activity by up to 70%, whereas peroxynitrite, a key mediator of NO-related oxidative stress, had excitotoxic effects. Antagonism of neuronal COS may therefore represent a novel approach to counteract neurohumoral activation in diseases such hypertension, obesity and heart failure.
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PMID:Mechanisms of action of nitric oxide in the brain stem: role of oxidative stress. 1214 34

Corticolimbic circuits involving the prefrontal cortex, amygdala, and ventral striatum determine the reward value of food and might play a role in environmentally induced obesity. Chemical manipulation of the nucleus accumbens shell (AcbSh) has been shown to elicit robust feeding and Fos expression in the hypothalamus and other brain areas of satiated rats. To determine the neurochemical phenotype of hypothalamic neurons receiving input from the AcbSh, we carried out c-Fos/peptide double-labeling immunohistochemistry in various hypothalamic areas known to contain feeding peptides, from rats that exhibited a significant feeding response after AcbSh microinjection of the GABA(A) agonist muscimol. In the perifornical area, a significantly higher percentage of orexin neurons expressed Fos after muscimol compared with saline injection. In contrast, Fos expression was not induced in melanin-concentrating hormone and cocaine-amphetamine-related transcript (CART) neurons. In the arcuate nucleus, Fos activation was significantly lower in neurons coexpressing CART and proopiomelanocortin, and there was a tendency for higher Fos expression in neuropeptide Y neurons. In the paraventricular nucleus, no significant activation of oxytocin and CART neurons was found. Thus AcbSh manipulation may elicit food intake through coordinated stimulation of hypothalamic neurons expressing orexigenic peptides and suppression of neurons expressing anorexigenic peptides. However, activation of many neurons not expressing these peptides suggests that additional peptides/transmitters in the lateral hypothalamus and accumbens projections to other brain areas might also be involved.
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PMID:Peptides that regulate food intake: appetite-inducing accumbens manipulation activates hypothalamic orexin neurons and inhibits POMC neurons. 1273 70

The neuropeptides orexins/hypocretins are essential for normal wakefulness and energy balance, and disruption of their function causes narcolepsy and obesity. Although much is known of the role of orexins in sleep/wake behavior, it remains unclear how they stimulate feeding and metabolism. One of the main targets of orexinergic neurons is the arcuate nucleus (ARC) of the hypothalamus, which plays a key role in feeding and energy homeostasis. By combining patch-clamp and RT-multiplex PCR analysis of individual neurons in mouse brain slices, we show that an electrophysiologically distinct subset of ARC neurons coexpress orexin receptors and glutamate decarboxylase-67 and are excited by orexin. Acting on postsynaptic orexin type 2 receptors, orexin activates a sodium-calcium exchange current, thereby depolarizing the cell and increasing its firing frequency. Because GABA is a potent stimulus for feeding, in both the ARC and its main projection site, these results suggest a mechanism for how orexin may control appetite.
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PMID:Orexin excites GABAergic neurons of the arcuate nucleus by activating the sodium--calcium exchanger. 1283 17


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