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

Hyperphagia and obesity can be experimentally induced in rodents by microinjection of 6-hydroxydopamine (6-OHDA) into the ventral noradrenergic bundle (VNAB) to interrupt efferent catecholaminergic pathways to the hypothalamus. Since hypothalamic neuropeptide Y (NPY) is implicated in the control of ingestive behavior, we evaluated hypothalamic NPY activity in this model of obesity. Adult male rats injected bilaterally with 12 microg of 6-OHDA in the VNAB displayed an enhanced rate of body weight gain and selective dark-phase hyperphagia that started at about 10 days postinjection and persisted for the entire duration of the experiment. NPY gene expression, assessed by ribonuclease protection assay, was significantly higher in the hypothalami of 6-OHDA-treated hyperphagic rats during the dark phase (p < 0.01 vs. levels during the light phase and in control, vehicle-injected rats). We also evaluated gene expression of NPY Y and Y5 receptors, receptor subtypes reported to mediate NPY-induced feeding. The dark-phase increase in NPY mRNA was accompanied by the concomitant upregulation of NPY Y5R gene expression, but not of Y1R mRNA levels. Leptin, the peripheral hormone secreted by adipocytes, is believed to maintain body weight and inhibit food intake, most likely by suppressing hypothalamic NPY activity. Evaluation of leptin gene expression in the epididymal fat revealed that the upregulation of leptin mRNA noted during the dark phase in control rats did not occur in 6-OHDA-treated rats. These observations implied that the normal restraint on NPY and feeding exercised by leptin in control rats may be abrogated in 6-OHDA-treated hyperphagic rats due to insufficient levels of leptin. If so, administration of leptin should inhibit food intake in these rats. Indeed, injection of leptin (2 mg/kg, intraperitoneally (i.p.)) on 2 consecutive days reduced 24-h food intake by 25% and significantly reduced body weight. These results suggest that the nocturnal hyperphagia and resultant obesity induced by 6-OHDA injected into the VNAB may be attributed to leptin deficiency concomitant with increased hypothalamic NPY.
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PMID:Evidence that dark-phase hyperphagia induced by neurotoxin 6-hydroxydopamine may be due to decreased leptin and increased neuropeptide Y signaling. 961 6

Two putative sympathetic nervous system (SNS) markers, noradrenaline and neuropeptide Y (NPY) were related to 24-h ambulatory blood pressure (BP) in 59 normotensive subjects, 34 non-insulin-dependent diabetics, and 25 controls. Plasma NPY levels were not significantly different between the two groups [non-insulin-dependent (NIDDM) diabetes mellitus 4.33 (3.25-5.78), controls 5.68 (3.39-6.97) p=0.26] as were those of noradrenaline (1.51+/-0.69 versus 1.78+/-0.55; p=0.053). There were correlations, controlled for age and obesity, of plasma NPY with clinic and night time diastolic BP in the control group only (r=0.49 [p=0.013] and r=0.48 [p=0.023] respectively). No similar correlation was found in the NIDDM group, or between plasma noradrenaline and blood pressure in either group. No correlation was found between plasma insulin and NPY or noradrenaline levels. There is a weak independent relationship between NPY and blood pressure in normotensive nondiabetics but not in NIDDM subjects. We found no evidence for the hypothesis that insulin modulates blood pressure through activity of the SNS.
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PMID:Lack of relationship between sympathetic nervous system activity, measured by two circulating markers, and blood pressure in diabetic and nondiabetic subjects. 961 69

Disruption of neural signaling by microinjection of a neurotoxin, colchicine (COL), in the ventromedial hypothalamus (VMH) of rats results in rapid and transient hyperphagia and body weight gain. Since neuropeptide Y (NPY) is a potent hypothalamic orexigenic signal and continuous NPY receptor activation by intracerebroventricular (icv) NPY infusion results in hyperphagia and obesity, we tested the hypothesis that altered NPYergic signaling may underlie the transient hyperphagia in COL-injected rats. Immediately following COL (4 microg) microinjections in the ventromedial nucleus (VMN) rats displayed hyperphagia both during the lights-on and lights-off periods. Concomitant with hyperphagia, preproNPY mRNA levels in the arcuate nucleus and NPY levels in the paraventricular nucleus decreased in a time-dependent manner. However, food intake in response to intracerebroventricular injections of NPY (29, 117 and 470 pmole) was significantly higher in COL-injected rats and the latency to initiation of feeding was markedly reduced as compared to controls. The smallest dose of NPY which was virtually ineffective in control rats, evoked near maximal intake in COL-injected rats. This enhanced response lasted for only 4 days paralleling the transient hyperphagia. The NPY Y1 receptor antagonist 1229U91 (5 or 30 microg/rat, icv) significantly suppressed feeding in COL-treated rats thereby indicating that hyperphagia in these rats was dependent upon endogenous NPY. Overall, these studies demonstrate that not only high levels, but low levels of NPY may also result in hyperphagia and increased body weight and this hyperphagia may be attributed to the rapid development of NPY Y1 receptor hypersensitivity.
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PMID:Increased receptor sensitivity to neuropeptide Y in the hypothalamus may underlie transient hyperphagia and body weight gain. 965 71

The treatment of obesity requires modulation of both energy intake and energy expenditure, and pharmaceutical treatments are being developed to complement the traditional means of dietary restriction and exercise. The recent discovery of the protein leptin, which modulates both food intake and energy expenditure, has provided a new tool with which to define and analyze potential pathways for pharmacological intervention. Neurotransmitters, such as neuropeptide Y (NPY) and norepinephrine, act downstream of leptin to modulate energy homeostasis. Specific subtypes of the receptors for these neurotransmitters represent promising molecular targets for the discovery of new drugs for the treatment of obesity.
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PMID:Molecular approaches to the discovery of new treatments for obesity. 966 52

The discovery of leptin has generated an extraordinary interest in the field of obesity but also in the understanding of the relationship between metabolic status and the neuroendocrine system. Following the initial demonstration that leptin administration to fasting mice can 'protect' neuroendocrine secretions and prevent the changes that are associated with fasting, the concept has emerged that a normal leptin secretion is a prerequisite for normal neuroendocrine secretions. Several unfavorable metabolic situations are associated with low plasma leptin, increased secretion of hypothalmic neuropeptide Y (NPY), and hypogonadism, and a causal relationship has been evoked. Severe dietary restriction in juvenile female rats is associated with low plasma leptin and sexual immaturity. Cessation of food restriction leads to immediate increase in plasma leptin followed 4 days later by vaginal opening. If food restriction is maintained, central leptin infusion can induce sexual maturation, thus demonstrating that leptin can act as a signal for the onset of puberty. In untreated type-I diabetic rats, hypogonadism is associated with very low plasma leptin and increased hypothalmic NYP synthesis and oestrous cyclicity. Fasting rapidly inhibits growth hormone (GH) secretion in association with low plasma leptin and elevated hypothalmic NPY. Central infusion of leptin to fasting rats was able to completely prevent the collapse of GH secretion and to maintain a normal low NPY synthesis. In summary, normally elevated plasma levels appear to be a prerequisite for normal GH and gonadotropin secretion in the rat. Degradation of metabolic conditions results in a rapid reduction of circulating leptin that could represent the signal for several alterations of neuroendocrine secretions. At the level of the hypothalamus, leptin could act on NPY neurons to transduce part or all of this 'metabolic' message. The possibility that changing plasma levels for leptin also affect peripheral endocrine targets, such as pituitary, ovary, adrenal or pancreas, is likely since these endocrine organs express functional long-term leptin receptors.
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PMID:Metabolic control of sexual function and growth: role of neuropeptide Y and leptin. 972 77

Although reduced biological activity of the obese gene product, leptin, has been associated with obesity, little information is available concerning leptin alterations during anorexia. Therefore, we measured circulating leptin concentrations and hypothalamic leptin binding in anorectic tumor-bearing and pair-fed control rats. Plasma concentrations of leptin decreased in tumor-bearing rats early in the course of tumor growth, and fell to nearly non-detectable levels during severe anorexia. The pair-fed control rats that ate the same amount of food as did the anorectic tumor-bearing rats exhibited a 50% decrease in plasma leptin concentration. Concentrations of free fatty acids were elevated in both tumor-bearing and pair-fed groups, while circulating levels of triglycerides were increased only in anorectic tumor-bearing rats. Leptin receptor density was doubled in the hypothalamus of tumor bearing rats, while binding affinity was decreased by 50%. These results suggest that peripheral leptin production is down-regulated, perhaps due to increased lipolysis in tumor-bearing rats. It appears that hypothalamic leptin systems up-regulate receptor numbers in response to decreased blood leptin level, however, the decrease in binding affinity may compensate for these alterations. Therefore, the influence of leptin on hypothalamic neuropeptide Y feeding systems may be minimal in anorectic tumor-bearing rats.
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PMID:Reciprocal changes in hypothalamic receptor binding and circulating leptin in anorectic tumor-bearing rats. 972 52

Modifications of (D-Trp32) neuropeptide Y (NPY) led to the development of potential peptide-based lower molecular weight (500-800 Da) NPY feeding antagonists. One compound, WRYamide (N-Ac-Trp-Arg-Tyr-NH2), blocked NPY-induced feeding for 1 to 4 h when injected intrahypothalamically (i.h.t.) at 1 to 40 microgram. Schedule-induced feeding was also antagonized for up to 24 h by 20 microgram of WRYamide, i.h.t. Injection of 2.5 mg/kg (1 mg/rat) of WRYamide, i.v., also reduced significantly schedule-induced feeding for 4 h. A conditioned taste aversion could not be classically conditioned to saccharin using WRYamide as the unconditioned stimulus. These results may lead to the development of systemically active anti-obesity drugs.
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PMID:WRYamide, a NPY-based tripeptide that antagonizes feeding in rats. 972 64

The tubby mouse is characterized by an autosomal recessive mutation which results in the development of maturity-onset obesity and sensorineural hearing loss and retinal degeneration. Although the tubby mutation which leads to a splicing defect of the tub gene has been identified recently, the mechanism by which it causes the obesity syndrome has not been established. In this study, the potential dysfunction of several hypothalamic neuroendocrine pathways involved in the central regulation of energy metabolism was investigated in tubby mice. In comparison with the wild-type controls, a significant reduction (20%) of pro-opiomelanocortin (POMC) mRNA expression was observed in the arcuate nucleus (ARC) of the mature, obese but not in the juvenile, non-obese tubby mice. Similarly, an age and body mass-dependent induction (about 30-fold) of neuropeptide Y (NPY) mRNA was observed in the dorsomedial (DMH) and ventromedial (VMH) hypothalamic nuclei of the tubby mice. However, NPY mRNA in the ARC was decreased by approximately 30 to 40% in both juvenile and mature tubby mice. The hypothalamic expression patterns of corticotropin releasing hormone (CRH) and the long form leptin receptor (OB-Rb) were not significantly altered in the mutant mice. These results suggest that the altered hypothalamic POMC and/or NPY functions may be important contributing factors for the development of obesity in this animal model.
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PMID:Evidence of altered hypothalamic pro-opiomelanocortin/ neuropeptide Y mRNA expression in tubby mice. 972 27

In insulin resistant subjects with android obesity the leptin levels are, as compared with non-obese subjects, elevated in proportion to their BMI, WHR and their percentage of body fat. Generally independent on obesity, leptin levels are significantly higher in women than in men as in women the percentage of adipose tissue is higher. After administration of 2 mg nicotine in Nicorette chewing gum to 36 android obese non-smokers the elevated baseline values of leptin did not change and thus the observation that cigarettes suppress hunger or that smoking promotes weight reduction is untrue or else this effect is not mediated by nicotine stimulation of leptin secretion or formation in adipose tissue, leptin being the adipose tissue hormone which controls food intake, the sensation of satiety and via neuropeptide Y also other hypothalamic functions such as muscular and sexual activity, gonadoliberin output, thermoregulation etc. Leptin thus offers no alibi to smokers. Conversely smoking in android obese hyperinsulinaemic hyperleptinaemic subjects with syndrome X (5H) potentiates significantly the risk of cardiovascular death.
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PMID:[The effects of nicotine on leptin levels in patients with android obesity]. 975 Apr 63

The regulation of body fat stores is a problem of energy and nutrient balance that can be most readily viewed as a feedback system. Several elements are involved in any feedback system, including afferent signals, a controller that senses the afferent signals and transduces their information and then activates efferent controls that regulate the controlled system. The recent discovery of leptin has provided a major missing link in the feedback control system. This afferent signal is produced exclusively in fat cells of nonpregnant mammals but can be produced in the placenta as well. This circulating peptide has a very strong relationship to the level of body fat and its absence experimentally and clinically produces massive obesity. In the controller, or brain, several anatomic regions play a central role in regulating fat stores. Damage to the ventromedial nucleus (VMH) or the paraventricular nucleus (PVN) in the hypothalamus produces massive obesity in mammals and birds. Injury to the central nucleus of the amygala will also produce obesity. In contrast, damage to the lateral hypothalamus reduces body fat. The syndrome of leptin deficiency or defects in the leptin receptors produce a massive obesity that is metabolically similar to the VMH or PVN lesion syndromes of obesity, suggesting that leptin may have its metabolic effects through these medial hypothalamic centers. Support for this idea has come from studies showing that damage to the PVN or VMH will block the effects of leptin. A number of neuropeptides and monoamines are involved with modulating of food intake and fat stores. Both serotonin, acting through 5-HT2C receptors, and norepinephrine, acting through beta 2 and/or beta 3 receptors, reduce food intake. A variety of peptides also influence food intake and body fat. Neuropeptide Y, dynorphin, galanin, and melanocyte-stimulating hormone all increase food intake. In contrast, a large number of peptides--including cholecystokinin, corticotrophin-releasing hormone/urocortin, enterostatin, insulin, leptin, alpha-MSH, and TRH--reduce food intake. Chronic administration of neuropeptide Y, acting through Y-5 receptors, can produce chronically increased food intake and obesity. This syndrome is similar to the VMH syndrome and suggests that NPY must be acting as an inhibitor of a feeding system. The melanocortin receptor system may be particularly important because a mouse that does not express MC4 receptors is massively overweight. These central systems modulate food intake and fat stores by the controlled system. Glucocorticoids from the adrenal gland are important in obesity, since adrenalectomy will reverse or prevent the development of all forms of obesity. The sympathetic nervous system is also important because low sympathetic activity is associated with experimental and clinical obesity. The reciprocal relationship between food intake and sympathetic activity has been a robust relationship, suggesting that beta receptors in the periphery or brain may be involved in feeding control. In one model of dietary obesity resulting when animals eat a high-fat diet, the syndrome is blocked by inhibitory adrenal steroid activity. These animals show a lower level of sympathetic activity and a low level of brain serotonin. Finally, they show an enhanced sensitivity to essential fatty acids when these are applied to the tongue or given into the gut. In this chapter, the control of energy stores as fat is viewed as a feedback system. Leptin is perceived as a key afferent signal and glucocorticoids and the sympathetic nervous system through beta receptors as essential elements of this control system.
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PMID:The MONA LISA hypothesis in the time of leptin. 976 5


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