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)

Hypothalamic neuropeptide Y (NPY) neurons are influenced by circulating levels of insulin and leptin and are thought to be involved in mediating hunger following underfeeding. We have investigated hypothalamic NPY receptor subtypes in lactating rats, which are markedly hyperphagic throughout the day and night. NPY receptors were measured by using [125I] peptide YY, a high-affinity ligand, and Y1 receptors were masked by using the highly specific antagonist BIBP 3226. Freely fed lactating rats showed no changes in the densities of Y1, or non-Y1, NPY binding sites in whole hypothalamic homogenates or in individual hypothalamic regions (measured by quantitative autoradiography) examined during the day or night (P > 0.05; n = 10/group, and n = 6/group, respectively). However, reducing food intake by 35% had a more profound effect on NPY receptor density in lactating than in control rats, producing down-regulation of non-Y1 receptors in the ventromedial, dorsomedial, and perifornical lateral areas (all P < 0.05; n = 7/group) and reduction of plasma insulin and leptin levels (both P < 0.01). Thus, although the NPY system may not have a major role in the hyperphagia of freely fed lactating rats, it appears to have an important function in the response to undernutrition in such animals.
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PMID:Neuropeptide Y receptor alterations in the hypothalamus of lactating rats. 1049 22

We recently reported on an elevation of neurons expressing the main orexigenic peptide neuropeptide Y (NPY) in the arcuate hypothalamic nucleus (ARC) of neonatally hyperinsulinaemic offspring of gestational diabetic mother rats (GD) at weaning. To investigate possible consequences, the long-term outcome of those animals was examined. At adult age, GD offspring showed hyperphagia (p < 0.001), basal hyperinsulinaemia (p < 0.05) and impaired glucose tolerance (p < 0.05), and were overweight (p < 0.01). This was accompanied by an elevated number of NPY neurons (p < 0.001) and galanin neurons (p < 0.001) in the ARC in adult GD offspring under basal conditions. These findings support our hypothesis on perinatally acquired, persisting malformation and/or malprogramming of peptidergic hypothalamic neurons in the offspring of GD mothers, possibly promoting the development of overweight and diabetogenic disturbances during life.
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PMID:Elevation of hypothalamic neuropeptide Y-neurons in adult offspring of diabetic mother rats. 1057 62

Hypothalamic neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH) influence feeding and levels of plasma glucose, insulin, free fatty acids, and triglycerides. Treatment of genetically obese, ob/ob mice, with dopamine receptor D(1)/D(2) agonists normalizes hyperphagia, body weight gain, hyperglycemia, and hyperlipidemia. We therefore examined whether levels of NPY and CRH immunoreactivity in discrete hypothalamic nuclei are altered in ob/ob mice, and whether dopaminergic treatment reverses this alteration. Female ob/ob mice were treated daily at 1 h after light onset with the D(1)/D(2) agonists, SKF-38393 (20 mg/kg) and bromocriptine (15 mg/kg), respectively or vehicle for 2 weeks. Such treatment, while normalizing body weight gain and hyperglycemia, also significantly reduced elevated NPY immunoreactivity in the suprachiasmatic (by 39%), intergeniculate (by 43%), paraventricular (PVN; by 31%), and arcuate (by 41%) nuclei in obese mice to levels observed in lean mice. This treatment also caused a 45-50% decline in levels of CRH in the PVN and dorsomedial hypothalamus compared to obese controls to levels observed in lean mice. Taken together, these findings suggest that dopaminergic D(1)/D(2) receptor coactivation may improve hyperphagia, hyperglycemia, and obesity in the ob/ob mouse, in part, by normalizing elevated levels of both NPY and CRH.
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PMID:Dopaminergic agonists normalize elevated hypothalamic neuropeptide Y and corticotropin-releasing hormone, body weight gain, and hyperglycemia in ob/ob mice. 1064 1

Moderately low levels of dietary protein are associated with increased food intake and body fat. We propose that the generation of this feeding signal is dependent on the level of dietary protein relative to the protein requirement of the animal, that is, that protein-dependent feeding is maximized when the level of dietary protein is around the animal's protein requirement. One of the factors that affects an animal's protein requirement is age. We predict that young, growing animals are more responsive to a moderately low level of dietary protein than are mature animals. The feeding response to moderately low dietary protein (10% casein) was determined in young ( approximately 190 g) and more mature ( approximately 340 g) Sprague-Dawley rats for 12 days. As an index of amino acid deamination, serum urea nitrogen concentrations were determined, as was the in vitro release of neuropeptide Y (NPY) from hypothalamic tissue containing the paraventricular nucleus. Young rats were more responsive to the feeding effects of moderately low dietary protein than mature animals. In young rats, cumulative food intake was inversely correlated with serum urea nitrogen concentration. No correlation was found in mature animals. Although the amount of NPY remaining in hypothalamic tissue after incubation was significantly greater (p = 0.04) in young rats fed 10% casein as compared with rats fed the standard 20% casein diet, no dietary difference in K(+)-stimulated NPY release was observed. We hypothesize that the signal for low-protein-induced hyperphagia is a reduction in a compound whose production is coupled to the level of amino acid deamination in the brain.
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PMID:Effects of age on the feeding response to moderately low dietary protein in rats. 1076 97

Chronic central administration of neuropeptide Y (NPY) causes hyperphagia, hyperinsulinemia, and obesity, a response that is prevented by prior adrenalectomy (ADX) in rats. The basis of NPY's effect and how the acute responses to this peptide are affected by ADX remain unknown. This study investigates the role of glucocorticoids in acute NPY-stimulated food intake, acute NPY-induced insulin release, and hypothalamic NPY-receptor mRNA expression levels. NPY-induced food intake was similar in ADX and control rats after acute intracerebroventricular injection of NPY. Injection of NPY caused a significant increase in plasma insulin in control rats, but this effect was completely absent in ADX rats in which basal plasma insulin levels were also lower than controls. In addition, ADX significantly reduced the number of neurons expressing NPY receptor Y(1) and Y(5) mRNAs in the ventromedial hypothalamus (VMH), without affecting Y(1)- or Y(5)-mRNA expression in the paraventricular hypothalamus or the arcuate nucleus. These data indicate that glucocorticoids are necessary for acute NPY-mediated insulin release and suggest that the mechanisms involve glucocorticoid regulation of Y(1) and Y(5) receptors specifically within the VMH nucleus.
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PMID:Adrenalectomy reduces neuropeptide Y-induced insulin release and NPY receptor expression in the rat ventromedial hypothalamus. 1079

Hypothalamic melanocortins are among several neuropeptides strongly implicated in the control of food intake. Agonists for melanocortin 4 (MC-4) receptors such as alpha-melanocyte-stimulating hormone (alpha-MSH), a product of proopiomelanocortin (POMC), reduce food intake, whereas hypothalamic agouti-related protein (AgRP) is a MC-4 receptor antagonist that increases food intake. To investigate whether reduced melanocortin signaling contributes to hyperphagia induced by uncontrolled diabetes, male Sprague-Dawley rats were studied 7 days after administration of streptozotocin (STZ) or vehicle. In addition, we wished to determine the effect of diabetes on muscle uncoupling protein 3 (UCP-3), a potential regulator of muscle energy metabolism. STZ diabetic rats were markedly hyperglycemic (31.3 +/- 1.0 mmol/l; P < 0.005) compared with nondiabetic controls (9.3 +/- 0.2 mmol/l). Insulin treatment partially corrected the hyperglycemia (18.8 +/- 2.5 mol/l; P < 0.005). Plasma leptin was markedly reduced in STZ diabetic rats (0.4 +/- 0.1 ng/ml; P < 0.005) compared with controls (3.0 +/- 0.4 ng/ml), an effect that was also partially reversed by insulin treatment (1.8 +/- 0.3 ng/ml). Untreated diabetic rats were hyperphagic, consuming 40% more food (48 +/- 1 g/day; P < 0.005) than controls (34 +/- 1 g/day). Hyperphagia was prevented by insulin treatment (32 +/- 2 g/day). In untreated diabetic rats, hypothalamic POMC mRNA expression (measured by in situ hybridization) was reduced by 80% (P < 0.005), whereas AgRP mRNA levels were increased by 60% (P < 0.01), suggesting a marked decrease of hypothalamic melanocortin signaling. The change in POMC, but not in AgRP, mRNA levels was partially reversed by insulin treatment. By comparison, the effects of diabetes to increase hypothalamic neuropeptide Y (NPY) expression and to decrease corticotropin-releasing hormone (CRH) expression were normalized by insulin treatment, whereas the expression of mRNA encoding the long form of the leptin receptor in the arcuate nucleus was unaltered by diabetes or insulin treatment. UCP-3 mRNA expression in gastrocnemius muscle from diabetic rats was increased fourfold (P < 0.005), and the increase was prevented by insulin treatment. The effect of uncontrolled diabetes to decrease POMC, while increasing AgRP gene expression, suggests that reduced hypothalamic melanocortin signaling, along with increased NPY and decreased CRH signaling, could contribute to diabetic hyperphagia. These responses, in concert with increased muscle UCP-3 expression, may also contribute to the catabolic effects of uncontrolled diabetes on fuel metabolism in peripheral tissues.
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PMID:Effects of streptozotocin-induced diabetes and insulin treatment on the hypothalamic melanocortin system and muscle uncoupling protein 3 expression in rats. 1086 41

A high fat diet leads to progressive development of obesity and leptin resistance in C57 mice with a middle stage of peripheral, but not central, leptin resistance. This stage is characterized by increased fat accumulation despite relative hypophagia. At a later stage central leptin resistance ensues along with hyperphagia, rapid weight and fat gain. The aim of this study is to characterize the mRNA levels of leptin receptor (LR), neuropeptide Y (NPY) and pro-opiomelanocortin (POMC) in high fat (HFF) and low fat (LFF) fed groups of mice. The hypothalamic arcuate nucleus (Arc) was investigated, as was the choroid plexus (ChP) in the case of the leptin receptor. No differences between groups were seen in LR, NPY or POMC mRNA levels after 1 week of feeding. After 8 and 19 weeks, the HFF mice, compared to LFF controls, demonstrated a +45% (P<0. 003) and +84% (P<0.0001) increase in the ratio of visceral fat to body weight and +223% (P<0.0001) and +468% (P<0.0001) elevation in plasma leptin levels, respectively. At 8 weeks, LR mRNA expression showed a +98% (P<0.016) and +66% (P<0.0001) increase in ChP and Arc, respectively, while Arc NPY mRNA showed down-regulation by -45% (P<0. 006). Arc POMC mRNA showed no significant changes between groups at 8 weeks. However, after long-term (19 weeks) feeding, the HFF mice displayed significantly -26% (P<0.039) and -33% (P<0.0015) reduced LR mRNA in the ChP and Arc, respectively, with Arc POMC and NPY mRNAs down by -55% (P<0.004) and -32% (P<0.009), respectively. The present results suggest that in the middle stage of development of high fat-induced obesity, when central leptin sensitivity is maintained, the increased leptin receptor expression may play a role to defend against obesity which is overwhelmed as central leptin insensitivity develops. In this later stage the down-regulation of the POMC system may be important in the final breakdown of weight homeostasis.
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PMID:Leptin receptor, NPY, POMC mRNA expression in the diet-induced obese mouse brain. 1096 2

Exposure to high-fat diets for prolonged periods results in positive energy balance and obesity, but little is known about the initial physiological and neuroendocrine response of obesity-susceptible strains to high-fat feeding. To assess responses of C57BL/6J mice to high- and low-fat diets, we quantitated the hypothalamic expression of neuropeptides implicated in weight regulation and neuroendocrine function over a 2-wk period. Exposure to high-fat diet increased food consumption over a 2-day period during which leptin levels were increased when assessed by a frequent sampling protocol [area under the curve (AUC): 134.6 +/- 10.3 vs. 100 +/- 12.3, P = 0.03 during first day and 126.5 +/- 8.2 vs. 100 +/- 5.2, P = 0.02 during second day]. During this period, hypothalamic expression of neuropeptide Y (NPY) and agouti-related protein (AgRP) decreased by approximately 30 and 50%, respectively (P < 0.001). After 1 wk, both caloric intake and hypothalamic expression of NPY and AgRP returned toward baseline. After 2 wk, cumulative caloric intake was again higher in the high-fat group, and now proopiomelanocortin (POMC) was elevated by 76% (P = 0.01). This study demonstrates that high-fat feeding induces hyperphagia, hyperleptinemia, and transient suppression of orexigenic neuropeptides during the first 2 days of diet. The subsequent induction of POMC may be a second defense against obesity. Attempts to understand the hypothalamic response to high-fat feeding must examine the changes as they develop over time.
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PMID:Differential expression of hypothalamic neuropeptides in the early phase of diet-induced obesity in mice. 1100 66

The injection of a melanocortin peptide or of melanocortin peptide analogues into the cerebrospinal fluid or into the ventromedial hypothalamus in nanomolar or subnanomolar doses induces a long-lasting inhibition of food intake. The effect keeps significant for up to 9 h and has been observed in all animal species so far tested, the most susceptible being the rabbit. The anorectic effect of these peptides is a primary one, not secondary to the shift towards other components of the complex melanocortin-induced behavioral syndrome, in particular grooming. The site of action is in the brain, and the effect is not adrenal-mediated because it is fully exhibited also by adrenalectomized animals. It is a very strong effect, because the degree of feeding inhibition is not reduced in conditions of hunger, either induced by 24 h starvation, or by insulin-induced hypoglycemia, or by stimulation of gamma-aminobutyric acid (GABA), noradrenergic or opioid systems. The microstructural analysis of feeding behavior suggests that melanocortins act as satiety-inducing agents, because they do not significantly modify the latencies to start eating, but shorten the latencies to stop eating. The mechanism of action involves the activation of melanocortin MC(4) receptors, because selective melanocortin MC(4) receptor antagonists inhibit the anorectic effect of melanocortins, while inducing per se a strong stimulation of food intake and a significant increase in body weight. Melanocortins seem to play an important role in stress-induced anorexia, because such condition, in rats, is significantly attenuated by the blockage of melanocortin MC(4) receptors; such a role is not secondary to an increased release of corticotropin-releasing factor (CRF), because, on the other hand, the CRF-induced anorexia is not affected at all by the blockage of melanocortin MC(4) receptors. The physiological meaning of the feeding inhibitory effect of melanocortins, and, by consequence, the physiological role of melanocortins in the complex machinery responsible for body weight homeostasis, is testified by the hyperphagia/obesity syndromes caused by mutations in the pro-opiomelanocortin (POMC) gene, or in the melanocortin MC(4) receptor gene, or in the agouti locus. Finally, recent evidences suggest that melanocortins could be involved in mediating the effects of leptin, and in controlling the expression of neuropeptide Y (NPY).
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PMID:Role of melanocortins in the central control of feeding. 1103 11

Recent technologic innovations have enabled probing the workings of individual cells and even molecules. As a result, our knowledge of the biological controls over eating and the regulation of body adiposity is increasing at a rapid pace. We review the evidence that food intake is controlled by separate but interacting groups of molecular signals. One group, termed satiety signals, are proportional to what is being consumed and help to determine meal size. Cholecystokinin is the best known of these, and its premeal administration causes a dose-dependent reduction of meal size. In and of itself, however, cholecystokinin (and other satiety signals) has little impact on body-fat stores. The second group, termed adiposity signals, circulate in proportion to body adiposity and enter the brain, where they interact with satiety signals in the brainstem and hypothalamus. Insulin and leptin are the best known of these adiposity signals, and the administration of either into the brain causes a dose-dependent reduction of both food intake and body weight. Within the brain, parallel but opposing pathways originating in the hypothalamic arcuate nuclei integrate adiposity signals with satiety signals. Those with a net anabolic effect increase food intake and reduce energy expenditure and are represented (among many such signals) by neuropeptide Y; those with a net catabolic effect decrease food intake and energy expenditure and are represented by brain melanocortins. This complex regulatory mechanism allows individuals to adapt their feeding schedule to idiosyncratic environmental constraints, eating whenever it is desirable or possible. Body-weight regulation occurs as adiposity signals alter the efficacy of meal-generated satiety signals.
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PMID:Adiposity signals and the control of energy homeostasis. 1105 94


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