Food intake in free-feeding and energy-deprived lean rats is mediated by the neuropeptide Y5 receptor.

Criscione, Leoluca; Rigollier, Pascal; Batzl‐Hartmann, Christine; Rueger, H.; Stricker–Krongrad, Alain; Wyss, P; Brunner, L; Whitebread, Steven; Yamaguchi, Yasuchika; Gerald, Christophe; Heurich, Rainer O.; Walker, Mary W.; Chiesi, Michele; Schilling, W; Hofbauer, Karl G.; Levens, Nigel

doi:10.1172/jci4188

Cited by 219 publications

(143 citation statements)

References 40 publications

(53 reference statements)

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“…The nonpeptide Y 5 -receptor antagonist CGP71683A is characterized by nanomolar affinity to the Y 5 -receptor subtype and only micromolar affinity to the other subtypes. This antagonist inhibits NPY induced food intake either in lean or obese rats, supporting the hypothesis that the Y 5 -receptor is involved in the regulation of feeding behaviour [29].…”

supporting

confidence: 71%

“…[Cys31,Pro34]pNPY (29), hardly changed the CD spectrum of pNPY, whereas [Phe32,Pro34]pNPY reduced dramatically the helicity of pNPY to 16%, mainly in favour of b sheet which increased to 55%. In these analogues again, affinity and secondary structure do not correlate, which suggests the importance of direct ligand±receptor interaction.…”

Section: Analogues With Replacements At Position 6±8 Of Npymentioning

confidence: 99%

“…Recent studies even suggest that different receptor subtypes redundantly mediate identical actions in a given system, as has been shown for the Y 1 -and Y 5 -receptor in the regulation of food intake [3]. Findings that deficiencies in either the Y 1 -or the Y 5 -receptors do not significantly impair the normal feeding response to fasting or NPY stimulation, strongly indicate that both Y receptors are involved in appetite regulation by NPY [29,30]. Selective receptor agonists or antagonists are useful tools with which to study the functions of a single receptor subtype.…”

mentioning

confidence: 91%

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Novel analogues of neuropeptide Y with a preference for the Y₁‐receptor

Söll

Dinger

Lundell

et al. 2001

European Journal of Biochemistry

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In contrast, cyclo S±S [Cys20,Cys24]pNPY was found to be a highly selective ligand at the Y 2 -receptor, binding only threefold less efficiently than NPY. Analogues containing variations of positions 31 and 32 showed highly reduced affinity to the Y 1 -receptor, while binding to the Y 5 -receptor was affected less. Inhibition of cAMP-accumulation of selected peptides with replacements within position 20±23 of NPY showed preserved agonistic properties. The NPY analogues tested give insights into ligand±receptor interaction of NPY at the Y 1 -, Y 2 -and Y 5 -receptor and contribute to our understanding of subtype selectivity. Furthermore, the Y 1 -receptor-preferring peptides are novel tools that will provide insight into the physiological role of the Y 1 -receptor.Keywords: food intake; neuropeptides; NPY; selective ligands; structure±affinity relationship.Obesity, food intake and energy homeostasis are key areas of growing importance because obesity is beginning to replace malnutrition and infectious diseases as the most significant contributor to ill health in the developed world [1]. Neuropeptide Y (NPY) is one of the most important effector molecules of leptin: it is a key molecule in the regulation of food intake, it acts via several different receptor subtypes and elicits several physiological effects. Profound effects on stimulation of food intake, secretion of luteinizing and growth hormone, and insulin release suggest an important role for NPY in the pathophysiology of obesity and diabetes [2±5]. A wide range of other effects of NPY have been reported, such as potent vasoconstriction [6], facilitation of learning and memory [7], modulation of locomotor behaviours [8], induction of hypothermia [9,10], inhibition of sexual behaviour [11], shifts in circadian rhythms [12], modulation of cardiorespiratory parameters[13], anxiolytic potency [14] and inhibition of alcohol consumption and resistance [15].NPY is a 36-amino acid peptide amide belonging to the family of pancreatic polypeptides that includes also pancreatic polypeptide (PP) and peptide YY; it was first isolated from pig brain in 1982 [16].NPY is widely distributed within the central nervous system and in the periphery. [25,26]. A putative Y 3 -receptor has been described only pharmacologically and no specific agonists or antagonists are known [27]. All receptors belong to the G-protein coupled receptor superfamily [28]. The correlation of a certain receptor subtype to a distinct physiological effect is not yet fully understood. Recent studies even suggest that different receptor subtypes redundantly mediate identical actions in a given system, as has been shown for the Y 1 -and Y 5 -receptor in the regulation of food intake [3]. Findings that deficiencies in either the Y 1 -or the Y 5 -receptors do not significantly impair the normal feeding response to fasting or NPY stimulation, strongly indicate that both Y receptors are involved in appetite regulation by NPY [29,30]. Selective receptor agonists or antagonists are useful tools with which to stu...

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supporting

confidence: 71%

Section: Analogues With Replacements At Position 6±8 Of Npymentioning

confidence: 99%

mentioning

confidence: 91%

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Novel analogues of neuropeptide Y with a preference for the Y₁‐receptor

Söll

Dinger

Lundell

et al. 2001

European Journal of Biochemistry

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“…NPY may partly drive the hyperphagia that contributes to obesity in these models, as food intake falls with administration of a potent Y5 antagonist (Criscione et al 1998), and in ob/ob mice that also have the NPY gene knocked out (Erickson et al 1996b). In these mutants NPY overactivity is clearly inappropriate to the nutritional needs of the animal, and presumably arises through interruption of the normal inhibitory influence of leptin, as a result of the ob mutation (which abolishes the production of biologically-active leptin) and the fa mutation (which affects the leptin receptor and reduces the animals' sensitivity to leptin; Phillips et al 1996;Dryden et al 1999).…”

Section: Neuropeptide Y and Obesitymentioning

confidence: 99%

The hypothalamus and the regulation of energy homeostasis: lifting the lid on a black box

2000

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The hypothalamus is the focus of many peripheral signals and neural pathways that control energy homeostasis and body weight. Emphasis has moved away from anatomical concepts of ‘feeding’ and ‘satiety’ centres to the specific neurotransmitters that modulate feeding behaviour and energy expenditure. We have chosen three examples to illustrate the physiological roles of hypothalamic neurotransmitters and their potential as targets for the development of new drugs to treat obesity and other nutritional disorders. Neuropeptide Y (NPY) is expressed by neurones of the hypothalamic arcuate nucleus (ARC) that project to important appetite-regulating nuclei, including the paraventricular nucleus (PVN). NPY injected into the PVN is the most potent central appetite stimulant known, and also inhibits thermogenesis; repeated administration rapidly induces obesity. The ARC NPY neurones are stimulated by starvation, probably mediated by falls in circulating leptin and insulin (which both inhibit these neurones), and contribute to the increased hunger in this and other conditions of energy deficit. They therefore act homeostatically to correct negative energy balance. ARC NPY neurones also mediate hyperphagia and obesity in the ob/ob and db/db mice and fa/fa rat, in which leptin inhibition is lost through mutations affecting leptin or its receptor. Antagonists of the Y5 receptor (currently thought to be the NPY ‘feeding’ receptor) have anti-obesity effects. Melanocortin-4 receptors (MC4-R) are expressed in various hypothalamic regions, including the ventromedial nucleus and ARC. Activation of MC4-R by agonists such as α-melanocyte-stimulating hormone (a cleavage product of pro-opiomelanocortin which is expressed in ARC neurones) inhibits feeding and causes weight loss. Conversely, MC4-R antagonists such as ‘agouti’ protein and agouti gene-related peptide (AGRP) stimulate feeding and cause obesity. Ectopic expression of agouti in the hypothalamus leads to obesity in the AVY mouse, while AGRP is co-expressed by NPY neurones in the ARC. Synthetic MC4-R agonists may ultimately find use as anti-obesity drugs in human subjects Orexins-A and -B, derived from prepro-orexin, are expressed in specific neurones of the lateral hypothalamic area (LHA). Orexin-A injected centrally stimulates eating and prepro-orexin mRNA is up regulated by fasting and hypoglycaemia. The LHA is important in receiving sensory signals from the gut and liver, and in sensing glucose, and orexin neurones may be involved in stimulating feeding in response to falls in plasma glucose.

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“…NPY regulates food intake (Stanley & Leibowitz, 1985;Criscione et al, 1998). In fact, it is the most potent orexigenic neuropeptide and may inhibit leptin-mediated satiety signal pathway with a mechanism so far unknown (Tomaszuk et al, 1996;Palmiter et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

The impact of the leucine 7 to proline 7 polymorphism of the neuropeptide Y gene on postprandial lipemia and on the response of serum total and lipoprotein lipids to a reduced fat diet

et al. 2002

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Objective: The aim of the study was to examine the impact of the leucine7 to proline7 (Leu7Pro) polymorphism of the NPY gene on postprandial (PP) lipemia, post-heparin plasma lipoprotein lipase (LPL) and hepatic lipase (HL) activities, and the response of serum lipids to a reduced fat diet. Design and subjects: Seven middle-aged obese subjects with Leu7Pro genotype were matched with seven subjects with Leu7Leu genotype for gender, age, apolipoprotein E phenotype and BMI. These 14 subjects participated in the oral 8 h fat tolerance test. Sixty-eight slightly obese middle-aged subjects (10 with the Leu7Pro genotype) had participated in intervention studies and consumed a reduced fat diet for 8 weeks.Results: There were no statistically significant differences in PP areas under the curve of plasma total triglycerides (TG), chylomicron TG, VLDL-TG or insulin between the genotype groups. The TG-to-cholesterol (C) ratio in VLDL was significantly lower in the subjects with Leu7Pro genotype compared to those with the Leu7Leu genotype at time points 30 min and 1 h in the fat tolerance test. Heparin-induced activities of LPL or HL or the response of serum total or LDL-C to the reduced fat diet did not differ between the groups. Conclusions: The NPY genotype neither affects the magnitude of postprandial lipemia induced by a fat tolerance test nor the response of serum total lipids or lipids in different lipoprotein classes to the reduced fat diet. However, this preliminary study suggests that there might be compositional differences in the lipoprotein particles between the genotype groups that affect postprandial lipid metabolism.

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Food intake in free-feeding and energy-deprived lean rats is mediated by the neuropeptide Y5 receptor.

Cited by 219 publications

References 40 publications

Novel analogues of neuropeptide Y with a preference for the Y₁‐receptor

Novel analogues of neuropeptide Y with a preference for the Y₁‐receptor

The hypothalamus and the regulation of energy homeostasis: lifting the lid on a black box

The impact of the leucine 7 to proline 7 polymorphism of the neuropeptide Y gene on postprandial lipemia and on the response of serum total and lipoprotein lipids to a reduced fat diet

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Food intake in free-feeding and energy-deprived lean rats is mediated by the neuropeptide Y5 receptor.

Cited by 219 publications

References 40 publications

Novel analogues of neuropeptide Y with a preference for the Y1‐receptor

Novel analogues of neuropeptide Y with a preference for the Y1‐receptor

The hypothalamus and the regulation of energy homeostasis: lifting the lid on a black box

The impact of the leucine 7 to proline 7 polymorphism of the neuropeptide Y gene on postprandial lipemia and on the response of serum total and lipoprotein lipids to a reduced fat diet

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Novel analogues of neuropeptide Y with a preference for the Y₁‐receptor

Novel analogues of neuropeptide Y with a preference for the Y₁‐receptor