Food intake regulation in rodents: Y<sub>5</sub>or Y<sub>1</sub>NPY receptors or both?

Duhault, J; Boulanger, Michèle; Chamorro, Susana; Boutin, Jean A.; Zuana, Odile Della; Douillet, Emmanuelle; Fauchère, Jean‐Luc; Félétou, Michel; Germain, Martine; Husson, Bruno; Vega, Antonio Monge; Renard, Pierre; Tisserand, F

doi:10.1139/y99-131

Cited by 44 publications

(28 citation statements)

References 32 publications

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“…Stimulation of food intake by central injections of NPY Y1 and Y5 agonists (12,38), inhibition of NPY-and fasting-induced increases in food intake by central injections of NPY Y1 and Y5 receptor antagonists (14,43), or injections of antisense oligonucleotides directed at these receptors (27) strongly implicate their involvement in NPY-induced hyperphagia, but not without some controversy (30). Nevertheless, collectively it appears that both of these receptors are involved in NPY-induced increases in food intake in laboratory rats and mice (18). In the present study, the Y5 receptor subtype seems considerably more closely linked to feeding, especially by hamsters in the 10 revolutions/pellet and blocked wheel groups, whereas the Y1 receptor agonist had virtually no effect on food intake.…”

Section: Discussionmentioning

confidence: 99%

Role of NPY and its receptor subtypes in foraging, food hoarding, and food intake by Siberian hamsters

Day

Keen-Rhinehart

Bartness

2005

American Journal of Physiology-Regulatory, Integrative and Comp

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Fasting has widespread physiological and behavioral effects such as increases in arcuate nucleus neuropeptide Y (NPY) gene expression in rodents, including Siberian hamsters. Fasting also stimulates foraging and food hoarding (appetitive ingestive behaviors) by Siberian hamsters but does relatively little to change food intake (consummatory ingestive behavior). Therefore, we tested the effects of third ventricular NPY Y1 ([Pro 34 ]NPY) or Y5 ]NPY) receptor agonists on these ingestive behaviors using a wheel running-based food delivery system coupled with simulated burrow housing. Siberian hamsters had 1) no running wheel access and free food, 2) running wheel access and free food, or 3) foraging requirements (10 or 50 revolutions/pellet). NPY (1.76 nmol) stimulated food intake only during the first 4 h postinjection (ϳ200 -1,000%) and mostly in hamsters with a foraging requirement. The Y1 receptor agonist markedly increased food hoarding (250 -1,000%), increased foraging as well as wheel running per se, and had relatively little effect on food intake (Ͻ250%). Unlike NPY, the Y5 agonist significantly increased food intake, especially in foraging animals (ϳ225-800%), marginally increased food hoarding (250 -500%), and stimulated foraging and wheel running 4 -24 h postinjection, with the distribution of earned pellets favoring eating versus hoarding across time. Across treatments, food hoarding predominated early postinjection, whereas food intake tended to do so later. Collectively, NPY stimulated both appetitive and consummatory ingestive behaviors in Siberian hamsters involving Y1/Y5 receptors, with food hoarding and foraging/wheel running (appetitive) more involved with Y1 receptors and food intake (consummatory) with Y5 receptors.appetitive; consummatory; wheel running; neuropeptide Y; Y1 and Y5 receptors ANIMAL BEHAVIORIST Wallace Craig in 1918 coined the terms "appetitive" and "consummatory" for the two-part sequence of eating, drinking, and sexual behaviors (13), referring to the seeking and completion of the goal object, respectively. In terms of appetitive ingestive behavior, this consists of food acquisition (foraging) and subsequent storage for future use (hoarding; for review, see Ref. 40), whereas consummatory ingestive behavior is feeding. Considerable effort has been made toward understanding the physiological mechanisms underlying consummatory ingestive behaviors, whereas much less is known about the physiological mechanisms underlying appetitive ingestive behaviors. We have been studying the appetitive ingestive behaviors of food hoarding (2, 3, 44) and, more recently, foraging (15-17) in Siberian hamsters (Phodopus sungorus). In most species, shortfalls in food availability trigger increases in foraging and increases in food intake once food is found, whereas in hamster species, including Siberian hamsters, fasting stimulates foraging and food hoarding with minimal increases in food intake (for review, see Ref. 16). To begin to discover the mechanisms underlying appetitive ingestive behaviors,...

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Section: Discussionmentioning

confidence: 99%

Role of NPY and its receptor subtypes in foraging, food hoarding, and food intake by Siberian hamsters

Day

Keen-Rhinehart

Bartness

2005

American Journal of Physiology-Regulatory, Integrative and Comp

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“…In this respect, the utility of receptor knockout mice to define the molecular mode of action of drugs cannot be overemphasized. The mechanism of action by which other NPY Y5 antagonists (47,48) reported to produce marked hypophagic effects in rodents is unknown, but notably no data have been presented to indicate that antagonism of NPY Y5 is their primary mode of action. We believe that the present data show convincingly that NPY5RA-972 potently antagonizes NPY Y5 receptors in the brain but fails to affect feeding in a variety of rat feeding models.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, a recent study of the effects of a selective NPY Y1 antagonist in NPY-treated wild-type, NPY Y1-deficient, and NPY Y5-deficient mice provides compelling evidence for the involvement of NPY Y1 in NPY-induced feeding (55). A number of other groups have shown that selective NPY Y1 antagonism inhibits NPY-induced feeding in rats (12,13,38,48).…”

Section: Discussionmentioning

confidence: 99%

Selective Antagonism of the NPY Y5 Receptor Does Not Have a Major Effect on Feeding in Rats

et al. 2002

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Neuropeptide Y (NPY) is thought to play a key role in stimulating feeding, thus making NPY receptors attractive appetite suppressant drug targets for treating obesity. Because the orexigenic effects of NPY have been ascribed to actions at the NPY Y5 receptor, we have determined the role of this receptor in feeding in rats, using a small molecule antagonist of this receptor. NPY5RA-972 is a selective and potent (<10 nmol/l) NPY Y5 receptor antagonist. This compound is central nervous system (CNS) penetrant, and an oral dose of 10 mg/kg NPY5RA-972 to rats produced concentrations in cerebrospinal fluid that greatly exceeded the in vitro IC 50 (inhibitory concentration 50%). Indeed, at doses to rats as low as 1 mg/kg, NPY5RA-972 inhibited feeding induced by intracerebroventricular (ICV) administration of a selective NPY Y5 agonist ([cPP 1-7 ,NPY 19 -23 , Ala 31 ,Aib 32 ,Gln 34 ]-hPP). However, in the dose range 1-10 mg/kg, NPY5RA-972 had no significant effect on food intake in Wistar rats induced to feed by either ICV NPY or 24 h fasting or in free-feeding Wistar or obese Zucker rats. Chronic administration of NPY5RA-972 (10 mg/kg twice daily) had no effect on food intake or body weight in either free-feeding Wistar rats or dietary obese rats. These data indicate that NPY5RA-972 is a potent, selective, orally active, and CNS-penetrant antagonist of the NPY Y5 receptor that prevents feeding driven by activation of this receptor. The data obtained with this antagonist indicate that the NPY Y5 receptor is not a major regulator of feeding in the rat. Diabetes 51: 2441-2449, 2002 R esearch into appetite control during the past decade has been ignited by the discovery of leptin and fueled by the recognition of obesity as a widespread and rapidly growing disease (1). Leptin is a fat-derived hormone that signals energy (fat) storage levels to the hypothalamus. A number of previously identified (e.g., neuropeptide Y [NPY], melaninconcentrating hormone, corticotropin-releasing factor, galanin, neuromedin U, bombesin and pro-opiomelanocortin peptides) and newly discovered (agouti-related protein, cocaine and amphetamine-regulated transcript, urocortin, orexin, ghrelin) neuropeptides have become recognized as central nervous system (CNS) targets of leptin action (2-5). Many of these peptides are known to influence feeding in experimental species, and their receptors have been proposed as possible targets for appetite suppressant drugs. Corroborative evidence supporting these hypotheses from human (6,7) and rodent mutations (8 -10) is limited, but compensation and redundancy have been invoked as explanations for unexpected negative findings (11). Ultimately, the generation of potent and selective modulators of these peptide pathways is key to our ability to explore the biology of appetite control and to defining which of these pathways are likely to be the best targets for appetite suppressant drugs.NPY is a 36 -amino acid peptide that is probably the most studied putative neuropeptide regulator of appetite. In rodents, NPY is e...

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“…It may turn out that combinations of NPY receptor antagonists represent the best approach to the modulation of the complex sequence of physiological and behavioral events that underlie normal and disordered appetite. 169 Clearly, care will also have to be exercised in the extrapolation of animal data using NPY antagonists to humans, where each NPY receptor subtype may have a different distribution and function. Therefore, the final answer as to whether any NPY receptor antagonist will be useful in the control of food intake, without producing unacceptable side effects, can only be definitively answered by clinical studies in man.…”

Section: Discussionmentioning

confidence: 99%

Appetite suppression based on selective inhibition of NPY receptors

Chamorro

Della‐Zuana

et al. 2002

Int J Obes

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AIM:The aim of this review is to critically assess available evidence that blockade of the actions of NPY at one of the five NPY receptor subtypes represents an attractive new drug discovery target for the development of an appetite suppressant drug. RESULTS: Blockade of the central actions of NPY using anti-NPY antibodies, antisense oligodeoxynucleotides against NPY and NPY receptor antagonists results in a decrease in food intake in energy-deprived animals. These results appear to show that endogenous NPY plays a role in the control of appetite. The fact that NPY receptors exist as at least five different subtypes raises the possibility that the actions of endogenous NPY on food intake can be adequately dissociated from other effects of the peptide. Current drug discovery has produced a number of highly selective NPY receptor antagonists which have been used to establish the NPY Y 1 receptor subtype as the most critical in regulating short-term food intake. However, additional studies are now needed to more clearly define the relative contribution of NPY acting through the NPY Y 2 and NPY Y 5 receptors in the complex sequence of physiological and behavioral events that underlie the long-term control of appetite. CONCLUSIONS: Blockade of the NPY receptor may produce appetite-suppressing drugs. However, it is too early to state with certainty whether a single subtype selective drug used alone or a combination of NPY receptor selective antagonists used in combination will be necessary to adequately influence appetite regulation.

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Food intake regulation in rodents: Y₅or Y₁NPY receptors or both?

Cited by 44 publications

References 32 publications

Role of NPY and its receptor subtypes in foraging, food hoarding, and food intake by Siberian hamsters

Role of NPY and its receptor subtypes in foraging, food hoarding, and food intake by Siberian hamsters

Selective Antagonism of the NPY Y5 Receptor Does Not Have a Major Effect on Feeding in Rats

Appetite suppression based on selective inhibition of NPY receptors

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Food intake regulation in rodents: Y5or Y1NPY receptors or both?

Cited by 44 publications

References 32 publications

Role of NPY and its receptor subtypes in foraging, food hoarding, and food intake by Siberian hamsters

Role of NPY and its receptor subtypes in foraging, food hoarding, and food intake by Siberian hamsters

Selective Antagonism of the NPY Y5 Receptor Does Not Have a Major Effect on Feeding in Rats

Appetite suppression based on selective inhibition of NPY receptors

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Resources

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Food intake regulation in rodents: Y₅or Y₁NPY receptors or both?