Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020505 (hyperphagia)
 6,116 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic obesity is associated with increased neuropeptide Y (NPY) messenger RNA (mRNA) and decreased POMC mRNA in the hypothalamus of ob/ob and db/db mice, or impaired sensitivity to alphaMSH (derived from POMC) in the yellow agouti mouse. Acquired obesity can be produced by chemically lesioning the hypothalamus with either monosodium glutamate (MSG) in neonates or gold thioglucose (GTG) in adult mice. The present study examined whether elevated NPY mRNA and/or decreased POMC mRNA in the hypothalamus are associated with obesity due to hypothalamic lesions. GTG injection into adult mice produced a profound obese phenotype, including hyperphagia, increased body weight, and increased leptin mRNA and peptide, in association with reduced hypothalamic NPY mRNA and POMC mRNA. MSG treatment produced virtual elimination of NPY mRNA in the arcuate nucleus and a reduction of hypothalamic POMC mRNA, and led to elevated leptin. MSG pretreatment did not attenuate GTG-induced hyperphagia and obese phenotype. These results do not support a role for NPY-synthesizing neurons in the arcuate nucleus in mediating hypothalamic acquired obesity, but are consistent with the hypothesis that decreased activity of hypothalamic neurons synthesizing POMC play a role in mediating hypothalamic obesity.
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PMID:Hyperphagia and weight gain after gold-thioglucose: relation to hypothalamic neuropeptide Y and proopiomelanocortin. 979 56

Brown adipose tissue-deficient [uncoupling protein (UCP)-promoter-driven diphtheria toxin A (DTA)] mice develop obesity as a result of both decreased energy expenditure and hyperphagia. The hyperphagia occurs despite high serum leptin levels. Hence, this is a model of leptin-resistant obesity in which the mechanism driving hyperphagia is unknown. Leptin is a regulator of a number of hypothalamic neuropeptides involved in energy homeostasis. In ob/ob mice, leptin deficiency results in increased expression of neuropeptide Y (NPY), agouti-related protein (AGRP), and melanin-concentrating hormone (MCH), and decreased expression of POMC. We have previously shown that NPY is reduced in the UCP-DTA mouse, suggesting a normal NPY response to leptin. To define other potential sites of leptin resistance, we used in situ hybridization to evaluate the expression of messenger RNAs (mRNAs) encoding a number of peptides, including NPY, AGRP, MCH, and POMC. We confirmed that the decrease in NPY expression previously detected by Northern blots reflects a decrease in NPY expression in the arcuate nucleus. AGRP mRNA was also decreased, whereas POMC mRNA levels in the arcuate nucleus were the same as control. MCH mRNA levels in the lateral hypothalamic area were also decreased. In contrast, there was induction of NPY expression in the dorsomedial hypothalamic nucleus in the UCP-DTA animals but not in the controls. The results indicate that these neuropeptides generally respond to leptin and that the hyperphagia seen in the UCP-DTA mice is likely the result of dysregulated expression of other, as yet unexamined, hypothalamic peptides, or lies at sites distal to the hypothalamus.
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PMID:Characterization of expression of hypothalamic appetite-regulating peptides in obese hyperleptinemic brown adipose tissue-deficient (uncoupling protein-promoter-driven diphtheria toxin A) mice. 979 75

Disruption of neural signaling in the ventromedial nucleus (VMN) of rats by microinjection of the neurotoxin colchicine (COL) results in transient hyperphagia accompanied by enhanced weight gain. We tested the hypothesis that release of neuropeptide Y (NPY), a potent orexigenic signal is augmented within the paraventricular nucleus (PVN) of COL-treated hyperphagic rats. Adult male rats were microinjected bilaterally with either COL (4 microg/0.5 microl in saline) or saline in the VMN and a push-pull guide cannula aimed at the PVN was implanted for analysis of extra-cellular NPY. COL-injected rats gained 37.8+/-6.1 g while the saline-injected rats lost 9.3+/-3.4 g during the 4 days following surgery. On day 4, post-injection, the PVN of these rats was perfused with artificial cerebrospinal fluid via the push-pull cannula. NPY levels in perfusates collected at 10 min intervals from hyperphagic, COL-injected rats were markedly diminished. Cumulative NPY efflux over the 180 min sampling period was significantly less in COL-treated (27.7+/-6.0 pg) versus saline-injected control rats (110.6+/-32.2 pg; P < 0.05). These results show that impairment of neural signaling in the VMN by COL suppressed NPY release in the PVN. These observations taken together with previous studies showing diminution in preproNPY mRNA in the arcuate nucleus (ARC) and NPY levels in the PVN are in accordance with the thesis that the VMN normally exerts a facilitatory influence on NPYergic signaling in the ARC-PVN axis.
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PMID:Neuropeptide Y release in the paraventricular nucleus is decreased during transient hyperphagia induced by microinjection of colchicine into the ventromedial nucleus of rats. 983 7

To elucidate the role of neuropeptide Y (NPY)-Y1 receptor (Y1-R) in food intake, energy expenditure, and other possible functions, we have generated Y1-R-deficient mice (Y1-R-/-) by gene targeting. Contrary to our hypothesis that the lack of NPY signaling via Y1-R would result in impaired feeding and weight loss, Y1-R-/- mice showed a moderate obesity and mild hyperinsulinemia without hyperphagia. Although there was some variation between males and females, typical characteristics of Y1-R-/- mice include: greater body weight (females more than males), an increase in the weight of white adipose tissue (WAT) (approximately 4-fold in females), an elevated basal level of plasma insulin (approximately 2-fold), impaired insulin secretion in response to glucose administration, and a significant changes in mitochondrial uncoupling protein (UCP) gene expression (up-regulation of UCP1 in brown adipose tissue and down-regulation of UCP2 in WAT). These results suggest either that the Y1-R in the hypothalamus is not a key molecule in the leptin/NPY pathway, which controls feeding behavior, or that its deficiency is compensated by other receptors, such as NPY-Y5 receptor. We believe that the mild obesity found in Y1-R-/- mice (especially females) was caused by the impaired control of insulin secretion and/or low energy expenditure, including the lowered expression of UCP2 in WAT. This model will be useful for studying the mechanism of mild obesity and abnormal insulin metabolism in noninsulin-dependent diabetes mellitus.
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PMID:Obesity and mild hyperinsulinemia found in neuropeptide Y-Y1 receptor-deficient mice. 986 Oct 26

The concept of interrelationships between the central nervous system and the periphery aimed at maintaining normal body weight homeostasis has been strengthened by the discovery of hypothalamic neuropeptide Y (NPY) and adipose tissue leptin. NPY, when infused intracerebroventricularly in normal animals produces hyperphagia and hormono-metabolic changes (hyperinsulinemia, hypercorticism) channeling nutrients preferentially toward lipogenesis and storage in adipose tissue and away from their utilization by muscles (muscle insulin resistance). Storage in NPY-infused rats is further favored by the observed decrease in the expression of uncoupling proteins. NPY-induced hyperinsulinemia and hypercorticosteronemia also promote leptin over-secretion. Released leptin, acting within the hypothalamus, decreases hypothalamic NPY levels (probably those of other hypothalamic neuropeptides as well), food intake, insulinemia, insulin sensitivity of white adipose tissue, while increasing that of muscles. Leptin acting centrally additionally favors the expression of uncoupling protein 1, 2, and 3, in keeping with an eflect on energy dissipating mechanisms. The respective hormono-metabolic eflects of NPY and leptin maintain a normal body homeostasis. In most obesity syndromes, the functional relationships between NPY and leptin are altered. Due to hypothalamic leptin receptor mutations or dysfunctions, leptin cannot exert its eflects: NPY levels (possibly those of other neuropeptides) remain elevated, maintaining excess storage, insulin as well as leptin resistance.
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PMID:[From Claude Bernard to the regulatory system between the hypothalamus and the periphery: implications for homeostasis of body weight and obesity]. 987 96

Electrolytic lesions placed in the ventromedial hypothalamus (VMH) of rats induce instant hyperphagia and excessive weight gain. Since neuropeptide Y (NPY) is a potent hypothalamic orexigenic signal, and leptin secreted by adipocytes regulates NPY output, we tested the hypothesis that altered NPYergic-leptin signaling may underlie hyperphagia in VMH-lesioned rats. VMH-lesioned rats exhibiting hyperphagia and excessive weight gain in a time-related fashion were sacrificed on days 2, 7, and 21 post-surgery. Quite unexpectedly, NPY concentrations in the hypothalamic paraventricular nucleus (PVN), a major site of NPY release for stimulation of feeding, and in other sites, such as the dorsomedial nucleus, lateral hypothalamic area and median eminence-arcuate nucleus decreased, with the earliest diminution occurring on day 2 in the PVN only. In vitro basal and K+-evoked NPY release from the PVN of VMH-lesioned rats was significantly lower than that of controls. Analysis of hypothalamic NPY gene expression showed that although the daily decrease in NPY mRNA from 0800 to 2200 h occurred as in control rats, NPY mRNA concentrations were markedly reduced at these times in the hypothalami of VMH-lesioned rats. Leptin synthesis in adipocytes as indicated by leptin mRNA levels was also profoundly altered in VMH-lesioned rats. The daily pattern of increase in adipocyte leptin mRNA at 2200 h from 0800 h seen in controls was abolished, higher levels of leptin gene expression at 2200 h were maintained at 0800 h. The pattern of increase in serum leptin and insulin levels diverged in VMH-lesioned rats. Serum insulin concentration increased to maximal on day 2 and remained at that level on day 21-post-lesion; serum leptin levels on the other hand, increased slowly in a time-related fashion during this period. These results demonstrate that hyperphagia and excessive weight gain in VMH-lesioned rats are associated with an overall decrease in hypothalamic NPY and augmented leptin signaling to the hypothalamus. The divergent time course of increases in serum leptin and insulin levels suggest independent mechanisms responsible for their augmented secretion, and neither these hormones nor VMH lesions altered the daily rhythm in NPY gene expression. These observations underscore the existence of an independent mechanism controlling the daily rhythm in hypothalamic NPY gene expression and suggest that leptin feedback action requires an intact VMH.
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PMID:Disruption in neuropeptide Y and leptin signaling in obese ventromedial hypothalamic-lesioned rats. 987 84

Effects of streptozotocin (STZ)-induced diabetes and insulin on opioid peptide gene expression were examined in rats. In experiment 1, three groups were administered STZ (75 mg/kg ip single injection). Two groups were killed at either 2 or 4 wk. In the third group, insulin treatment (7.0 IU/kg x 1 day for 3 wk) was initiated 1 wk after STZ injection. STZ induced hyperphagia and reduced weight gain. Insulin decreased food intake and increased body weight relative to diabetes. Proopiomelanocortin (POMC) mRNA in arcuate nucleus (Arc) and pituitary decreased in diabetes and normalized after insulin treatment. Prodynorphin (proDyn) mRNA increased in diabetes and normalized in the pituitary after insulin but not in the Arc. Diabetes did not alter proenkephalin (proEnk) expression in the Arc or pituitary, nor dynorphin A1-17 or beta-endorphin in paraventricular nucleus (PVN). alpha-Melanocyte-stimulating hormone (alpha-MSH) peptide levels were decreased in the PVN and normalized following insulin treatment. Diabetes increased Arc neuropeptide Y mRNA, and insulin suppressed this increase. In experiment 2, insulin (2.5 IU/kg sc) daily for 1 wk in normal rats increased Arc POMC mRNA, but not proDyn and proEnk mRNA. These results suggest that Arc POMC expression and PVN alpha-MSH peptide levels decrease in diabetes. Also, insulin may influence Arc and pituitary POMC activity in neurons that regulate energy metabolism.
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PMID:STZ-induced diabetes decreases and insulin normalizes POMC mRNA in arcuate nucleus and pituitary in rats. 1023 22

The objective of this study was to determine whether neuropeptide Y (NPY) and recombinant human interleukin-1 receptor antagonist (IL-1ra) would: first, increase food intake; secondly, decrease concentrations of GH; thirdly, reduce GHRH-induced release of GH; and fourthly, reduce changes to concentrations of IGF-I in plasma during experimental endotoxemia in sheep. Six treatments were given to six castrated male sheep in a 6x6 Latin square treatment order. Osmotic mini-pumps were implanted at 0 h and a jugular vein was cannulated. Each sheep was continuously infused with saline (0.9%) or lipopolysaccharide (LPS) (20 micrograms/kg per 24 h, s.c.) at 10 microliters/h for 72 h via the osmotic mini-pumps. Blood samples (3 ml) were collected at 15-min intervals from 24 to 33 h. At 26 h, one of three treatments (artificial cerebrospinal fluid, NPY or IL-1ra) was injected i.c.v. within 30 s (0.3 microgram/kg), then infused i.c.v. from 26 to 33 h (600 microliters/h) at 0.3 microgram/kg per h. GHRH was injected i.v. (0.075 microgram/kg) at 32 h after which blood samples were collected at 5, 10, 15, 30, 45 and 60 min. Feed intake was reduced up to 50% for 48 h in LPS-treated compared with non-LPS-treated sheep. NPY restored feed intake in LPS-treated sheep and induced hyperphagia in non-LPS-treated sheep from 24 to 48 h. In contrast, IL-1ra did not affect appetite. Injection of NPY increased concentrations of GH from 26 to 27 h, while IL-1ra had no effect. Infusion of NPY suppressed GHRH-induced release of GH. However, no treatment altered pulse secretion parameters of GH. Concentrations of IGF-I were 20% higher at 72 h in LPS-treated sheep given NPY than in sheep treated with LPS alone, and this may reflect increased appetite from 24 to 48 h. We concluded that reduced appetite during endotoxemia is due to down-regulation of an NPY-mediated mechanism. Furthermore, NPY stimulates release of GH in healthy sheep, does not reduce pulse secretion parameters of GH, but does suppress GHRH-induced release of GH in endotoxic sheep. Therefore, NPY may be an important neurotransmitter linking appetite with regulation of GH during endotoxemic and healthy states in sheep.
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PMID:Neuropeptide Y restores appetite and alters concentrations of GH after central administration to endotoxic sheep. 1032 Aug 32

It has been reported that hyperphagia and excessive body weight gain of genetically obese rodents were abolished by adrenalectomy. High hypothalamic levels of neuropeptide Y (NPY) were found in obese rodents. A chronic intracerebroventricular (icv) infusion of NPY in normal rats was shown to produce most hormono-metabolic abnormalities of genetically obese animals, and to be inefficient in doing so in adrenalectomized (ADX) rats. The combined presence of NPY and of glucocorticoids thus appeared to be necessary for inducing obesity. This study, therefore, was aimed at determining the consequences of a chronic i.c.v. NPY infusion in ADX rats receiving or not i.c.v. glucocorticoids. It was found that the combined i.c.v. infusion of NPY and dexamethasone in ADX rats increased food intake, body weight, plasma insulin, leptin, and triglyceride levels relative to vehicle-infused ADX controls. The infusion of NPY alone, or of dexamethasone alone in ADX rats failed to produce these effects. In contrast, the icv infusion of NPY alone greatly decreased the expression of brown adipose tissue uncoupling protein-1 and -3. This was not modified by the superimposed infusion of dexamethasone. It is concluded that, although many of centrally elicited NPY effects require the central presence of glucocorticoids, those bearing on the inhibition of uncoupling proteins expression (energy dissipation) do not require central glucocorticoids.
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PMID:Selective dependence of intracerebroventricular neuropeptide Y-elicited effects on central glucocorticoids. 1038 13

We have studied the hypothalamic activity of the neuropeptide Y (NPY) system in dietary-induced obese male Wistar rats and examined whether the NPY antagonist, BW1229U91, can inhibit the hyperphagia during positive energy balance associated with feeding rats an energy-rich, highly palatable diet. Rats given a highly palatable, high-fat diet became obese after 8 weeks and exhibited hyperinsulinemia and hyperleptinemia, as compared to lean rats fed on standard pellet laboratory diet. Hypothalamic NPY mRNA concentrations were significantly reduced by approximately 70% in dietary-obese rats compared with lean controls, and the former were hypersensitive to intracerebroventricular injections of NPY, possibly as a result of NPY receptor up-regulation. Intracerebroventricular injections of BW 1229U91, that inhibits food intake in starved rats, did not alter food intake in either control or obese rats fed either standard pellet diet or the highly palatable diet, respectively. We conclude that dietary-obese rats have underactive hypothalamic NPYergic neurons compared to lean controls, possibly as a result of increased plasma concentrations of leptin and/or insulin that directly inhibit the NPY neuronal activity. The lack of effect of BW1229U91 on the increased caloric intake of dietary-obese rats suggests that the hyperphagia is not NPY-driven and supports the data indicating reduced synaptic activity of the hypothalamic NPY system.
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PMID:Hypothalamic NPY status during positive energy balance and the effects of the NPY antagonist, BW 1229U91, on the consumption of highly palatable energy-rich diet. 1044 95


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