Neuropeptide Y Induced Feeding in the Rat Is Mediated by a Novel Receptor<sup>1</sup>

O’Shea, Donal; Morgan, David; Meeran, Karim; Edwards, C. M. B.; Turton, M. D.; Choi, Sanghee; Heath, Martha E.; Gunn, I.; Taylor, Gillian; Howard, Jane K.; Bloom, CI; Small, Caroline J.; Haddo, Omar; J., J.; Callinan, W.; Smith, David M.; Ghatei, Mohammad A.; Bloom, Stephen R.

doi:10.1210/endo.138.1.4899

Cited by 79 publications

(30 citation statements)

References 37 publications

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“…After this period, rats were given a further week of daily handling to habituate them to all experimental procedures and minimize stress. A positive dipsogenic response to ICV injection of angiotensin II (ANG II; 150 ng/rat), as previously described (16,40,41), verified cannula placement. If an animal ate <10 g of food in a 24-h period or lost >10 g body wt over a 48-h period, it was considered unwell and excluded from the study.…”

Section: Methodsmentioning

confidence: 75%

Effects of Chronic Central Nervous System Administration of Agouti-Related Protein in Pair-Fed Animals

Small

Kim²,

Stanley³

et al. 2001

Diabetes

146

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The melanocortin receptor (MC3-R and MC4-R) antagonist, agouti-related protein (AGRP), is a potent stimulant of food intake. We examined the effect of chronic intracerebroventricular (ICV) AGRP treatment on energy metabolism and pituitary function in ad libitum fed rats and rats administered AGRP and then pair-fed to a saline control group. Chronic ICV AGRP (83-132) administration (1 nmol/day for 7 days) significantly increased food intake and body weight in ad libitum fed animals compared with saline-treated controls (body weight on day 7: 272 ± 6 [saline] vs. 319 ± 8 g [AGRP ad libitum fed]; P < 0.001). A significant increase in the epididymal fat pad weight, interscapular brown adipose tissue (BAT) weight, and plasma leptin was also observed in the ad libitum fed group. In the AGRP pair-fed group, a significant increase in the epididymal fat pad weight, BAT weight, and plasma leptin was again observed, suggesting that AGRP caused metabolic changes independent of increased food intake. BAT uncoupling protein 1 (UCP-1) content was significantly decreased compared with saline controls in both the AGRP ad libitum fed (21 ± 8% of saline control; P < 0.01) and AGRP pair-fed groups (24 ± 7% of saline control; P < 0.01). Plasma thyroid-stimulating hormone (TSH) was significantly suppressed compared with saline controls in both the AGRP ad libitum fed and AGRP pair-fed groups (3. T he hypothalamic melanocortin system is a regulator of energy homeostasis. The agouti-related protein (AGRP), produced in the arcuate nucleus, is an antagonist at the melanocortin 3 and 4 receptors (MC3-R and MC4-R), which are distributed throughout the brain. The proopiomelanocortin (POMC) products, such as ␣-melanocyte-stimulating hormone (␣-MSH), act as agonists at the melanocortin receptors (1-3). Hypothalamic POMC mRNA, AGRP mRNA, and the density of MC4-R have been shown to be altered with nutritional status (4,5). Defects of POMC processing and mutations of MC4-R in humans and mice are associated with gross obesity (6-11).5Administration of the synthetic MC3/4-R agonist MT II into the forebrain ventricles or directly into the paraventricular nucleus (PVN) of the hypothalamus of rats or mice produced a dosage-dependent reduction in food intake and body weight (12)(13)(14). A single injection of either the endogenous (AGRP ) or the synthetic (SHU9119 and HS014) MC3/4-R antagonists stimulated food intake in rodents (12,13,15,16). Chronic administration of the more selective MC4-R antagonist, HS028, for 7 days via an osmotic minipump significantly increased food intake and body weight. Tachyphylaxis to HS028 did not occur. However, neither energy expenditure nor pituitary function were examined in this study (17). Previous results from this department have demonstrated that AGRP (83-132), the endogenous hypothalamic melanocortin receptor antagonist, significantly increased 24-h food intake and antagonized the anorectic effects of ␣-MSH (16).The melanocortin system also influences energy expenditure. Intracerebroventricular (ICV) administra...

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Section: Methodsmentioning

confidence: 75%

Effects of Chronic Central Nervous System Administration of Agouti-Related Protein in Pair-Fed Animals

Small

Kim²,

Stanley³

et al. 2001

Diabetes

146

View full text Add to dashboard Cite

show abstract

“…The entire injection process lasted under 2 min, and the rats were returned to their cages with the minimum of disruption. Correct placement of the cannula into the third cerebral ventricle was confirmed by injection of angiotensin II (150 ng) as described previously (18). Animals not displaying a prompt and sustained drinking response were excluded from further study.…”

Section: Intracerebroventricular (Icv) and Inter-pvn Cannulation Andmentioning

confidence: 99%

AMP-activated Protein Kinase Plays a Role in the Control of Food Intake

Andersson

Filipsson

Abbott

et al. 2004

Journal of Biological Chemistry

686

562

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AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that actsas an intracellular energy sensor maintaining the energy balance within the cell. The finding that leptin and adiponectin activate AMPK to alter metabolic pathways in muscle and liver provides direct evidence for this role in peripheral tissues. The hypothalamus is a key regulator of food intake and energy balance, coordinating body adiposity and nutritional state in response to peripheral hormones, such as leptin, peptide YY-(3-36), and ghrelin. To date the hormonal regulation of AMPK in the hypothalamus, or its potential role in the control of food intake, have not been reported. Here we demonstrate that counter-regulatory hormones involved in appetite control regulate AMPK activity and that pharmacological activation of AMPK in the hypothalamus increases food intake. In vivo administration of leptin, which leads to a reduction in food intake, decreases hypothalamic AMPK activity. By contrast, injection of ghrelin in vivo, which increases food intake, stimulates AMPK activity in the hypothalamus. Consistent with the effect of ghrelin, injection of 5-amino-4-imidazole carboxamide riboside, a pharmacological activator of AMPK, into either the third cerebral ventricle or directly into the paraventricular nucleus of the hypothalamus significantly increased food intake. These results suggest that AMPK is regulated in the hypothalamus by hormones which regulate food intake. Furthermore, direct pharmacological activation of AMPK in the hypothalamus is sufficient to increase food intake. These findings demonstrate that AMPK plays a role in the regulation of feeding and identify AMPK as a novel target for anti-obesity drugs. AMP-activated protein kinase (AMPK)1 plays a pivotal role in the regulation of energy metabolism and has been dubbed a cellular fuel gauge (1). AMPK is activated following an increase in the AMP:ATP ratio within the cell that occurs following a decrease in ATP levels (2, 3). Once activated, AMPK switches on ATP-generating (catabolic) pathways, e.g. fatty acid oxidation, and switches off ATP-using pathways (anabolic) pathways, e.g. fatty acid synthesis, allowing the cell to restore its energy balance (2, 3). In addition to acute effects on metabolism, AMPK has more long term effects, altering both gene (4) and protein expression (5, 6). Recent results have demonstrated activation of AMPK in the absence of changes in adenine nucleotide levels, indicating that there may be multiple pathways upstream of AMPK (7,8). The molecular mechanisms leading to activation of AMPK have not been fully elucidated, but it is clear that activation of AMPK requires phosphorylation of threonine 172 (Thr 172 ) within the activation loop segment of the catalytic (␣) subunit (9, 10). Very recently, LKB1, a protein kinase that is inactivated in a hereditary form of cancer termed Peutz-Jeghers syndrome, was shown to account for most of the AMPK kinase activity in cell extracts (11,12) raising the possibility that AMPK could l...

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“…However, like Y 5 receptors, ARC Y 1 receptor numbers, distribution and mRNA, are reduced during fasting, an effect which is attenuated by administration of glucose (Cheng et al 1998). Furthermore, NPY fragments with weak affinity to the Y 1 receptor still elicit a similar dose-dependent increase in food intake to NPY, suggesting that the Y 1 receptor may not be mediating its effect (O'Shea et al 1997). Y 1 receptor-deficient mice are obese, but are not hyperphagic, suggesting that the Y 1 receptor may affect energy expenditure rather than feeding (Kushi et al 1998).…”

Section: Hypothalamic Neuropeptidesmentioning

confidence: 99%

Appetite control

Wynne¹,

Stanley²,

McGowan³

et al. 2005

Journal of Endocrinology

475

410

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Our understanding of the physiological systems that regulate food intake and body weight has increased immensely over the past decade. Brain centres, including the hypothalamus, brainstem and reward centres, signal via neuropeptides which regulate energy homeostasis. Insulin and hormones synthesized by adipose tissue reflect the long-term nutritional status of the body and are able to influence these circuits. Circulating gut hormones modulate these pathways acutely and result in appetite stimulation or satiety effects. This review discusses central neuronal networks and peripheral signals which contribute energy homeostasis, and how a loss of the homeostatic process may result in obesity. It also considers future therapeutic targets for the treatment of obesity.

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Neuropeptide Y Induced Feeding in the Rat Is Mediated by a Novel Receptor¹

Cited by 79 publications

References 37 publications

Effects of Chronic Central Nervous System Administration of Agouti-Related Protein in Pair-Fed Animals

Effects of Chronic Central Nervous System Administration of Agouti-Related Protein in Pair-Fed Animals

AMP-activated Protein Kinase Plays a Role in the Control of Food Intake

Appetite control

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Neuropeptide Y Induced Feeding in the Rat Is Mediated by a Novel Receptor1

Cited by 79 publications

References 37 publications

Effects of Chronic Central Nervous System Administration of Agouti-Related Protein in Pair-Fed Animals

Effects of Chronic Central Nervous System Administration of Agouti-Related Protein in Pair-Fed Animals

AMP-activated Protein Kinase Plays a Role in the Control of Food Intake

Appetite control

Contact Info

Product

Resources

About

Neuropeptide Y Induced Feeding in the Rat Is Mediated by a Novel Receptor¹