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)

We have attempted to provide a progress report on current research on the role of catecholamines and serotonin receptor subtypes in feeding control. Recent evidence suggests that only some of the several catecholamine receptor subtypes are specifically involved in feeding control. They include the beta 1/2-adrenoceptors, the alpha 1-adrenoceptors and the D1 dopamine receptors: stimulation of these receptors reduces feeding in rats. Stimulation of serotonergic 5-HT1B and 5-HT2C receptors reduces feeding and perhaps enhances the satiating effect of food. Recently, an interesting reciprocal relation between serotonin and cholecystokinin has been discovered in relation to feeding control. The serotonergic 5-HT2A receptors are involved in stress-induced anorexia and regulate the hyperphagia induced by neuropeptide Y in the nucleus paraventricularis of the hypothalamus. Both effects may involve changes in the secretion of corticotropin-releasing factor. These findings may help elaborate neuronal models of feeding control and perhaps facilitate progress in the pharmacotherapy of human obesity and eating disorders.
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PMID:Pharmacology of ingestive behaviour. 876 44

Neurons containing serotonin (5-HT), a potent anorexic agent, come into contact with neuropeptide Y-ergic neurons, that project from the arcuate nucleus (ARC) to the paraventricular nucleus (PVN). NPY powerfully stimulates feeding and induces obesity when injected repeatedly into PVN. We hypothesize that 5-HT tonically inhibits the ARC-PVN neurons and that balance between the two systems determines feeding and energy homeostasis. This study aimed to determine whether central injection of the 5-HT synthesis inhibitor p-chlorophenylalanine (pCPA), which increases feeding, increased hypothalamic NPY and NPY mRNA levels. pCPA (10 mg/kg in 3 microliters) was administered into the third ventricle either as a single injection (n = 8) or daily for 7 days (n = 8). Control rats received a similar injection of saline. pCPA significantly increased food intake compared with controls after both single and repeated injections (P < 0.05). NPY levels were measured by radioimmunoassay in microdissected hypothalamic extracts. NPY levels in the acutely treated group were significantly increased in the paraventricular nucleus (PVN; by 41%, P = 0.01), anterior hypothalamic area (AHA; by 34%, P < 0.01) and lateral hypothalamic area (LHA; by 41%, P < 0.02). In the 7-day-treated group, NPY levels were also increased in the same areas, i.e. PVN (by 24%, P < 0.01), AHA (by 30%, P < 0.01) and LHA (by 38%, P = 0.01). There were no significant changes in the ARC or any other region or in hypothalamic NPY mRNA levels. pCPA administration increased NPY levels in several regions notably the PVN. This is a major site of NPY release, where NPY injection induces feeding. We suggest that the hyperphagia induced by pCPA is mediated by increased NPY levels and secretion in the PVN. This is further evidence for interactions between NPY and 5-HT in the control of energy homeostasis.
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PMID:Increased feeding and neuropeptide Y (NPY) but not NPY mRNA levels in the hypothalamus of the rat following central administration of the serotonin synthesis inhibitor p-chlorophenylalanine. 882 73

Concentrations of the potent hypothalamic appetite stimulating peptide neuropeptide Y (NPY), and its mRNA, are increased in rats with experimental diabetes, suggesting a role in the hyperphagia of this disorder. The 2-h feeding responses to intracerebroventricular (i.c.v.) injection of neuropeptide Y (NPY) (5, 10, and 15 mu g doses) were measured in male Wistar rats treated with streptozotocin (55 mg/kg) to induce diabetes. Streptozotocin-diabetic rats given i.c.v. NPY exhibited reduced feeding responses compared to controls (P < 0.05). Dexamethasone treated rats exhibit similar changes in NPY content and mRNA in the hypothalamus to those seen in diabetes, but are not hyperphagic. Feeding responses were also measured in this model, to assess whether high levels of endogenous NPY might account for the reduced response in diabetes. In contrast, the feeding response to NPY in comparison to controls was unaltered in dexamethasone treated rats. To investigate whether altered NPY receptor number or affinity, was the underlying mechanism for these divergent responses, receptor binding experiments were performed using (125)I-PYY and membranes prepared from rat hypothalamus. No significant difference was found in receptor number or affinity between the 2 groups (B(max): 114.7 +/- 18.9 vs 127.4 +/- 27.1 fmol/mg protein, K(d): 99.6 +/- 28.2 vs 135.1 +/- 32.4 pM). Similarly no difference was found between hypothalamic membranes prepared from dexamethasone-treated and control animals. NPY receptor subtypes in the hypothalamus were compared with that of cortex (predominantly Y1) and hippocampus (predominantly Y2) using the Y1-specific ligand [Leu(31)Pro(34)] NPY. These studies showed that the binding profile in the hypothalamus most closely matched that in the hippocampus, suggesting that the majority of hypothalamic receptors were of the Y2 subtype. Receptor autoradiography revealed low binding in the hypothalamus, and particularly in the paraventricular nucleus of the hypothalamus. Competition with [Leu(31)Pro(34)] NPY confirmed that only a low density of binding to Y1 like receptors was present in the hypothalamus. No difference was observed between control and streptozotocin treated animals. The feeding response to exogenous NPY is reduced in experimental diabetes, but not in dexamethasone treated rats. These differing responses do not appear to be due to altered NPY receptor number or affinity in the hypothalamus.
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PMID:Reduced NPY induced feeding in diabetic but not steroid-treated rats: lack of evidence for changes in receptor number or affinity. 886 Dec 84

Acute administration of neuropeptide Y into the hypothalamus or cerebral ventricles produces hyperphagia and hyperinsulinemia. However, it is not known to what extent the hyperinsulinemia depends on the food intake. Consequently, serum insulin and glucose, as well as food and water consumption, were measured over 3 h, following injection of 1-20 micrograms neuropeptide Y into the third ventricle of adult female rats. In the presence of food, 1-10 micrograms neuropeptide Y produced a dose-dependent increase in food and water intake and serum insulin. Insulin levels were closely correlated with the quantity of food ingested. In the absence of food, 1-20 micrograms neuropeptide Y produced a dose-dependent increase in water intake, whereas 1-5 micrograms produced a does-dependent increase in serum insulin. We concluded that ICV neuropeptide Y can stimulate insulin secretion even at low doses and this response does not completely depend on food intake.
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PMID:Intracerebroventricular neuropeptide Y produces hyperinsulinemia in the presence and absence of food. 887 37

We determined the changes in neuropeptide Y (NPY) mRNA expression of the arcuate nucleus (ARC) in sham-operated (SHAM) and bilaterally ovariectomized (OVX) rats with estradiol (E2) supplement. Ovariectomy increases body weight gain for 3 weeks, accompanied by an increase of daily food intake. Ovariectomy significantly reduced serum corticosterone levels. E2 supplement reversed the effects of ovariectomy on body weight gain, food intake and serum corticosterone levels. Ovariectomy significantly increased NPY mRNA expression in the ARC. E2 supplement decreased NPY mRNA expression in the ARC of OVX rats. The present findings indicated that hypothalamic NPY mRNA expression, which involves the regulation of feeding behavior, are in parallel with circulating estrogen levels. Hypothalamic NPY mRNA expression may be important in the induction of hyperphagia after the withdrawal of estrogen by bilateral ovariectomy.
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PMID:Withdrawal of [corrected] estrogen increases hypothalamic neuropeptide Y (NPY) mRNA expression in ovariectomized obese rat . 892 83

Dominant alleles at the agouti locus (A) cause an obesity syndrome in the mouse, as a consequence of ectopic expression of the agouti peptide. This peptide, normally only found in the skin, is a high-affinity antagonist of the melanocyte-stimulating hormone receptor (MC1-R), thus explaining the inhibitory effect of agouti on eumelanin pigment synthesis. The agouti peptide is also an antagonist of the hypothalamic melanocortin-4 receptor (MC4-R). To test the hypothesis that agouti causes obesity by antagonism of hypothalamic melanocortin receptors, we identified cyclic melanocortin analogues that are potent agonists or antagonists of the neural MC3 (refs 11, 12) and MC4 receptors. Intracerebroventricular administration of the agonist, MTII, inhibited feeding in four models of hyperphagia: fasted C57BL/6J, ob/ob, and A(Y) mice, and mice injected with neuropeptide Y. Co-administration of the specific melanocortin antagonist and agouti-mimetic SHU9119 completely blocked this inhibition. Furthermore, administration of SHU9119 significantly enhanced nocturnal feeding, or feeding stimulated by a prior fast. Our data show that melanocortinergic neurons exert a tonic inhibition of feeding behaviour. Chronic disruption of this inhibitory signal is a likely explanation of the agouti obesity syndrome.
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PMID:Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. 899 Jan 9

Over the years, the work of research laboratories in Baton Rouge (USA), Seattle (USA) and Geneva (Switzerland) have reached analogous conclusions regarding the main etiology of obesity as studied in animals: it largely lies within the brain, notably within the hypothalamus. The hypothalamus is indeed known to modulate food intake and energy partitioning, while the periphery has also been proposed to feed-back on the central nervous system (CNS) to provide information on the state of body energy stores, the two together constituting a loop system connecting the brain to the periphery (1,2,3). This etiologic viewpoint of a pivotal role of the hypothalamus in obesity syndromes has been strengthened by the discovery of one hypothalamic neuropeptide and one peripheral (adipose tissue) hormone, respectively neuropeptide Y (4), and quite particularly, leptin (5). As neuropeptide Y produces hyperphagia (6, 7) and as leptin produces hypophagia in normal animals (8,9,10), the loop system just mentioned was thought to comprise functional relationships, at least between these two factors. Other evidence also suggested that such a loop system was altered in obese animals.
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PMID:The loop system between neuropeptide Y and leptin in normal and obese rodents. 901 34

The discovery of both neuropeptide Y and of leptin has led to a better understanding of the pathophysiology of obesity syndromes in animal models. It has strengthened the concept of the importance of the hypothalamus in the etiology of these syndromes. Due to alterations in the regulation of the hypothalamus, e.g. by insulin, by leptin or by decreases in the availability of glucose in specific brain areas, most animal models of obesity have higher than normal hypothalamic neuropeptide Y levels. As neuropeptide Y is a potent orexigenic agent, this hypothalamic defect explains why obese rodents are hyperphagic. Increased hypothalamic neuropeptide Y levels produce hyperinsulinemia and hypercorticism, two abnormalities previously reported in obesity, but whose origin is now known to be driven by neuropeptide Y. As hyperinsulinemia favors lipid accretion and muscle insulin resistance, and as hypercorticism favors the occurrence of both high circulating triglyceride levels and muscle insulin resistance, it may be appreciated that most disorders previously reported in obesity can now be explained by high hypothalamic neuropeptide Y levels. Leptin, produced and secreted by adipose tissue, is a potent anorectic agent whose main action is exerted within the hypothalamus in which it has been shown to decrease neuropeptide Y, therefore food intake. Leptin secretion is favored, in particular, by insulin as well as by glucocorticoids. When leptin is administered to obese mice of the ob/ob strain (which do not produce nor secrete leptin due to a gene mutation), their food intake, body weight and most metabolic abnormalities are normalized. However, in the majority of genetically obese rodents, as well as in obese humans, circulating levels of leptin are high. This is related to hyperinsulinemia- and hypercorticosteronemia-induced leptin oversecretion, as well as to central leptin receptor dysfunctions preventing normal leptin access to and action within specific brain areas. Under these conditions and to prevent the effects of elevated hypothalamic neuropeptide Y levels, neuropeptide Y antagonists or active leptin agonists must be found. Neuropeptide Y and leptin further underline the existence of functional relationship between the brain (hypothalamus) and the periphery (adipose tissue, muscle). Lack of leptin (mutated leptin gene) or inefficient leptin action (leptin receptor defect) results in increased hypothalamic neuropeptide Y levels. The latter favor hyperinsulinemia and hypercorticism both producing oversecretion of leptin which, when inefficient, cannot decrease neuropeptide Y: a vicious circle is created which maintains either a "thrifty phenotype" favoring fat depot or overt obesity, depending on the degree of hyperphagia.
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PMID:Central nervous system and body weight regulation. 923 33

The fatty Zucker rat has impaired heat production and fails to mount an adequate thermogenic response to cold exposure, partly because of decreased sympathetic drive to thermogenesis in brown adipose tissue. Neuropeptide Y, synthesized in neurons of the hypothalamic arcuate nucleus and released in the paraventricular nucleus, stimulates feeding and inhibits brown adipose tissue activity. The neuropeptide Y neurons are overactive in fatty Zucker rats and are thought to contribute to hyperphagia, reduced energy expenditure and obesity. We have examined the relationship between thermogenic activity in brown adipose tissue (measured as uncoupling protein messenger RNA levels) and hypothalamic neuropeptide Y and neuropeptide Y messenger RNA levels in response to cold exposure (4 degrees C) for 2.5 and 18 h, in fatty and lean Zucker rats. In lean Zucker rats, cold exposure at 4 degrees C for 2.5 and 18 h significantly increased uncoupling protein messenger RNA levels by 3.5-fold (P<0.01) and 3.3-fold (P<0.01), respectively, compared with warm-maintained controls. Exposure to cold for 18 h also increased neuropeptide Y concentrations in the paraventricular nucleus (P<0.01) and ventromedial nucleus (P<0.001) in lean rats, with no change in neuropeptide Y messenger RNA after either 2.5 or 18 h. By contrast, fatty Zucker rats showed no significant changes in uncoupling protein messenger RNA (P>0.05) at either duration of cold exposure. There were also no significant changes in neuropeptide Y levels in any region nor in neuropeptide Y messenger RNA, with cold exposure for either period (P>0.05). In lean rats, cold exposure therefore stimulates brown fat uncoupling protein messenger RNA and also increases neuropeptide Y concentrations in its hypothalamic sites of release. We suggest that increased brown fat thermogenic capacity induced by cold in lean rats may be mediated, at least in part, by decreased neuropeptide Y release in the paraventricular nucleus, resulting in its accumulation in this site. Defective thermogenic responses in fatty rats may result from central dysregulation of brown adipose tissue due to sustained and non-suppressible overactivity of hypothalamic neuropeptide Y neurons.
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PMID:Role of hypothalamic neuropeptide Y neurons in the defective thermogenic response to acute cold exposure in fatty Zucker rats. 925 38

1. The thiazolidinedione BRL 49653 (rosiglitazone) induces hyperphagia and weight gain in obese, insulin-resistant fatty Zucker rats but not in lean insulin-sensitive rats. We investigated whether these responses might involve neuropeptide Y (NPY), leptin and insulin. 2. BRL 49653 (1 mg kg(-1) day(-1), orally) was given for 7 or 20 days to fatty and lean Zucker and Wistar rats. 3. In lean rats of either strain, BRL 49653 had no effect on food intake, body weight, plasma insulin and corticosterone, NPY or NPY mRNA levels. 4. Fatty rats given BRL 49653 showed a 30% increase in food intake and accelerated body weight gain (both P<0.01) after 7 and 20 days, but without significant changes in regional hypothalamic NPY or NPY mRNA levels. 5. Plasma leptin levels were twice as high in untreated fatty Zucker rats as in lean rats (P<0.01), but were unaffected by BRL 49653 given for 20 days. However, BRL 49653 reduced insulin levels by 42% and increased corticosterone levels by 124% in fatty rats (both P<0.01). 6. Hyperphagia induced in fatty Zucker rats by BRL 49653 does not appear to be mediated by either a fall in circulating leptin levels or increased activity of hypothalamic NPYergic neurones. The fall in plasma insulin and/or rise in corticosterone levels during BRL 49653 treatment may be involved, consistent with the postulated role of these hormones in the control of food intake.
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PMID:Increased feeding in fatty Zucker rats by the thiazolidinedione BRL 49653 (rosiglitazone) and the possible involvement of leptin and hypothalamic neuropeptide Y. 942 Dec 88


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