UMLS:C0028754 - FACTA Search

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Query: UMLS:C0028754 (obesity)
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Neuropeptide Y (NPY), a 36-amino-acid neuromodulator abundantly expressed in the brain, has been implicated in the regulation of food intake and body weight. Pharmacological data suggest that NPY's stimulatory effect on appetite is transduced by the G-protein-coupled NPY Y5 receptor (Y5R). We have inactivated the Y5R gene in mice and report that younger Y5R-null mice feed and grow normally; however, they develop mild late-onset obesity characterized by increased body weight, food intake and adiposity. Fasting-induced refeeding is unchanged in younger Y5R-null mice and they exhibit normal sensitivity to leptin. Their response to intracerebroventricular (i.c.v.) administration of NPY and related peptides is either reduced or absent. NPY deficiency attenuates the obesity syndrome of mice deficient for leptin (ob/ob), but these effects are not mediated by NPY signaling through the Y5R because Y5R-null ob/ob mice are equally obese. These results demonstrate that the Y5R contributes to feeding induced by centrally administered NPY and its analogs, but is not a critical physiological feeding receptor in mice.
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PMID:Role of the Y5 neuropeptide Y receptor in feeding and obesity. 962 73

The regulation of body fat stores is a problem of energy and nutrient balance that can be most readily viewed as a feedback system. Several elements are involved in any feedback system, including afferent signals, a controller that senses the afferent signals and transduces their information and then activates efferent controls that regulate the controlled system. The recent discovery of leptin has provided a major missing link in the feedback control system. This afferent signal is produced exclusively in fat cells of nonpregnant mammals but can be produced in the placenta as well. This circulating peptide has a very strong relationship to the level of body fat and its absence experimentally and clinically produces massive obesity. In the controller, or brain, several anatomic regions play a central role in regulating fat stores. Damage to the ventromedial nucleus (VMH) or the paraventricular nucleus (PVN) in the hypothalamus produces massive obesity in mammals and birds. Injury to the central nucleus of the amygala will also produce obesity. In contrast, damage to the lateral hypothalamus reduces body fat. The syndrome of leptin deficiency or defects in the leptin receptors produce a massive obesity that is metabolically similar to the VMH or PVN lesion syndromes of obesity, suggesting that leptin may have its metabolic effects through these medial hypothalamic centers. Support for this idea has come from studies showing that damage to the PVN or VMH will block the effects of leptin. A number of neuropeptides and monoamines are involved with modulating of food intake and fat stores. Both serotonin, acting through 5-HT2C receptors, and norepinephrine, acting through beta 2 and/or beta 3 receptors, reduce food intake. A variety of peptides also influence food intake and body fat. Neuropeptide Y, dynorphin, galanin, and melanocyte-stimulating hormone all increase food intake. In contrast, a large number of peptides--including cholecystokinin, corticotrophin-releasing hormone/urocortin, enterostatin, insulin, leptin, alpha-MSH, and TRH--reduce food intake. Chronic administration of neuropeptide Y, acting through Y-5 receptors, can produce chronically increased food intake and obesity. This syndrome is similar to the VMH syndrome and suggests that NPY must be acting as an inhibitor of a feeding system. The melanocortin receptor system may be particularly important because a mouse that does not express MC4 receptors is massively overweight. These central systems modulate food intake and fat stores by the controlled system. Glucocorticoids from the adrenal gland are important in obesity, since adrenalectomy will reverse or prevent the development of all forms of obesity. The sympathetic nervous system is also important because low sympathetic activity is associated with experimental and clinical obesity. The reciprocal relationship between food intake and sympathetic activity has been a robust relationship, suggesting that beta receptors in the periphery or brain may be involved in feeding control. In one model of dietary obesity resulting when animals eat a high-fat diet, the syndrome is blocked by inhibitory adrenal steroid activity. These animals show a lower level of sympathetic activity and a low level of brain serotonin. Finally, they show an enhanced sensitivity to essential fatty acids when these are applied to the tongue or given into the gut. In this chapter, the control of energy stores as fat is viewed as a feedback system. Leptin is perceived as a key afferent signal and glucocorticoids and the sympathetic nervous system through beta receptors as essential elements of this control system.
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PMID:The MONA LISA hypothesis in the time of leptin. 976 5

Neuropeptide Y (NPY), a 36 amino acid neuromodulator that is secreted by neurons throughout the peripheral and central nervous system, has been implicated in the control of many physiological processes. We have begun to examine its role in regulation of appetite, behavior, and excitotoxicity by examining mice that are unable to produce NPY as a consequence of gene inactivation. These mutant mice are remarkably normal when reared under standard vivarium conditions. Despite considerable evidence that NPY plays a central role in stimulating appetite, NPY-deficient mice eat normally, grow normally, and refeed after a fast normally. Furthermore, all of their endocrine responses to fasting are normal. The response of NPY-null mice to diet-induced obesity, chemically induced obesity (monosodium glutamate and gold thioglucose), and genetic-based obesity (lethal yellow agouti, Ay; uncoupling protein-diphtheria toxin transgenics, UCP-DT) were all normal. However, NPY deficiency does partially ameliorate the obesity and all of the adverse endocrine effects of leptin deficiency in ob/ob mice. NPY-null mice as well as mice deficient in both NPY and leptin are more sensitive to leptin, suggesting that NPY may normally have a tonic inhibitory action on leptin-mediated satiety signals. NPY-null mice display the normal voracious feeding response to injected NPY. Thus, the only condition where we have observed a role for NPY in body-weight regulation is in the context of complete leptin deficiency--where absence of NPY is beneficial. The activity and general behavior of NPY-null mice are normal. They appear to have normal spatial and contextual learning ability; however, they manifest more anxiety under some conditions. NPY-null mice occasionally display spontaneous, seizure-like events. They also are less able to terminate seizures induced by GABA receptor antagonists or glutamate receptor agonists. These observations are consistent with previous data suggesting that NPY plays an important role in dampening excitotoxicity.
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PMID:Life without neuropeptide Y. 976 8

Intracerebroventricular administration of neuropeptide Y to normal rats induces a syndrome characterised by obesity, hyperinsulinaemia, insulin resistance and over expression of the adipose tissue ob gene. Little is known about the effect of circulating neuropeptide Y on glucose metabolism, insulin secretion and leptin. We therefore aimed to evaluate the effect of an intravenous infusion of neuropeptide Y on glucose disposal, endogenous glucose production, whole body glycolytic flux, and glucose storage as assessed during euglycaemic hyperinsulinaemic clamp. In addition, the insulin-stimulated glucose utilisation index in individual tissues was measured by the 2-deoxy-[1-3H]-glucose technique. The effect of neuropeptide Y on insulin secretion was evaluated by hyperglycaemic clamp. Infusion did not induce any change in endogenous glucose production during basal conditions or at the end of the clamp. Glucose disposal was significantly increased in the rats given neuropeptide Y compared with controls (27.8 +/- 1.3 vs 24.3 +/- 1.6 mg x min(-1) x kg(-1); p < 0.05) as was the glycolytic flux (18.9 +/- 1.6 vs 14.4 +/- 0.8 mg x min(-1) x kg(-1); p < 0.05), while glucose storage was comparable in the two groups. In skeletal muscle, the glucose utilisation index was increased significantly in rats given neuropeptide Y. The glucose utilisation index in subcutaneous and epididimal adipose tissue was not significantly different between the two groups. Plasma leptin was significantly increased by hyperinsulinaemia, but was not affected by neuropeptide Y infusion. Both the early and late phase of the insulin response to hyperglycaemia were significantly reduced by neuropeptide Y. In conclusion neuropeptide Y infusion may increase insulin-induced glucose disposal in normal rats, accelerating its utilisation through the glycolytic pathway. Neuropeptide Y reduces both phases of the insulin response to hyperglycaemia.
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PMID:Effects of intravenous neuropeptide Y on insulin secretion and insulin sensitivity in skeletal muscle in normal rats. 983 45

High serum levels of total and LDL cholesterol are important risk factors in the development of atherosclerotic coronary artery disease. Cholesterol metabolism is affected by nutritional, environmental and genetic factors. Neuropeptide Y (NPY), which is widely expressed in both the central and peripheral nervous systems, has an important role in the hypothalamic regulation of energy balance by stimulating food intake and favoring energy storage through increased lipoprotein lipase activity in white adipose tissue. As a part of ongoing study of the genetic basis of obesity, we screened the NPY gene for sequence variants. We report here the identification of a common Leu(7)-to-Pro(7) polymorphism in the signal peptide of NPY. Presence of this Pro(7) in NPY was associated with higher serum levels of total and LDL cholesterol in obese subjects participating in two independent Finnish and Dutch studies. Furthermore, normal-weight Finns with Pro(7) also had higher serum levels of total and LDL cholesterol than did subjects with Leu(7)/Leu(7), as analyzed in three subsequent determinations at 5-year intervals during a 10-year follow-up period. The NPY polymorphism was not associated with higher cholesterol levels in normal-weight Dutch. Our study provides evidence that NPY is linked to cholesterol metabolism and that the polymorphism producing Pro(7) in NPY is one of the strongest genetic factors identified thus far affecting serum cholesterol, particularly in obese subjects.
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PMID:Association of a leucine(7)-to-proline(7) polymorphism in the signal peptide of neuropeptide Y with high serum cholesterol and LDL cholesterol levels. 984 84

The offspring of diabetic mothers is at increased risk to develop obesity and diabetogenic disturbances during life. Pathophysiological mechanisms responsible are unclear. Neuropeptide Y (NPY) is an important hypothalamic stimulator of food intake and body weight gain, and its levels are decreased by elevated insulin. In neonatally hyperinsulinaemic offspring of diabetic mother rats, hypothalamic insulin level was significantly increased at birth (p < 0.01). At weaning, i.e. at the end of the critical hypothalamic differentiation period, a significantly increased number of NPY-positive neurons (p < 0.01) appeared in the arcuate hypothalamic nucleus. In conclusion, an increase in the number of NPYergic neurons in the hypothalamus, possibly due to hypothalamic malformation and/or perinatally acquired hypothalamic insulin resistance, might contribute to the development of obesity and metabolic disturbances in the offspring of diabetic mothers.
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PMID:Hypothalamic insulin and neuropeptide Y in the offspring of gestational diabetic mother rats. 992 49

Galanin is a pleiotropic neuroendocrine signal produced in discrete subpopulations of neurons distributed in several sites in the hypothalamus. Neuropeptide Y and beta-endorphin also display pleiotropism, but they are produced by subpopulations of neurons located only in the arcuate nucleus of the hypothalamus. Each of these neuropeptides exerts a regulatory influence on reproduction and appetitive behavior. Experimental and morphologic evidence from our laboratory show direct contacts and interplay among these diverse signals. Seemingly, an interconnected network composed of these three neuropeptide-producing neurons provides precision and site specificity in the relay of information necessary to govern reproduction and appetite. Disruptions in this interplay are likely to manifest in untoward consequences such as infertility and obesity.
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PMID:Neuroendocrine interactions between galanin, opioids, and neuropeptide Y in the control of reproduction and appetite. 992 74

Leptin inhibits feeding and decreases body weight. It may act partly by inhibiting hypothalamic neurons that express neuropeptide Y, a powerful inducer of feeding and obesity. These neuropeptide Y neurons express the Ob-Rb leptin receptor and are overactive in the fatty (fa/fa) Zucker rat. The fa mutation affects the extracellular domain of the leptin receptor, but its impact on leptin action and neuropeptide Y neuronal activity is not fully known. We compared the effects of three doses of leptin given intracerebroventricularly and three doses of leptin injected intraperitoneally on food intake and hypothalamic neuropeptide Y mRNA, in lean and fatty Zucker rats. In lean rats, 4-h food intake was reduced in a dose-related fashion (P<0.01) by all intracerebroventricular leptin doses and by intraperitoneal doses of 300 and 600 microg/kg. Neuropeptide Y mRNA levels were reduced by 28% and 21% after the highest intracerebroventricular and intraperitoneal doses respectively (P<0. 01 for both). In fatty rats, only the highest intracerebroventricular leptin dose reduced food intake (by 22%; P<0. 01). Neuropeptide Y mRNA levels were 100% higher in fatty rats than in lean animals, and were reduced by 18% (P<0.01) after the highest intracerebroventricular leptin dose. Intraperitoneal injection had no effect on food intake and neuropeptide Y mRNA. The fa/fa Zucker rat is therefore less sensitive to leptin given intracerebroventricularly and particularly intraperitoneally, suggesting that the fa mutation interferes both with leptin's direct effects on neurons and its transport into the central nervous system. Obesity in the fa/fa Zucker rat may be partly due to the inability of leptin to inhibit hypothalamic neuropeptide Y neurons.
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PMID:Divergent effects of intracerebroventricular and peripheral leptin administration on feeding and hypothalamic neuropeptide Y in lean and obese (fa/fa) Zucker rats. 1002 67

Obesity is a serious health problem in the Western societies, therefore its treatment has become the subject of intense interest in the scientific community. A significant number of recent publications enlist different central and peripheral factors which play important roles in the regulation of food intake, body weight and energy expenditure. Neuropeptide Y, a 36 amino acid peptide, which is quite abundant in the brain, seems to be one of the more important players in these regulations. Recently five NPY receptors have been cloned and pharmacological evidence strongly supports the existence of a sixth receptor. There are many contradictory findings regarding which NPY receptor mediates the effect of NPY on food intake. This article will review the effects of NPY on the regulation of food intake and energy expenditure and will discuss the pharmacological and molecular evidence as to which NPY receptor(s) mediate this effect. The review will also summarize the progress which has been made in the design of novel NPY-ergic ligands, especially NPY receptor antagonists, for potential use in the treatment of obesity.
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PMID:Central control of feeding behavior by neuropeptide Y. 1019 48

Neuropeptide Y (NPY) is known to induce robust feeding through the action of NPY receptors in the hypothalamus. Among the subtypes of NPY receptors, Y(1) receptors may play a key role in feeding regulation. In the present study, we demonstrated that a novel Y(1) antagonist, J-104870, shows high selectivity and potency for the Y(1) receptor with an anorexigenic effect on NPY-mediated feeding. J-104870 displaced [(125)I]peptide YY (PYY) binding to cloned human and rat Y(1) receptors with K(i) values of 0.29 and 0.54 nM, respectively, and inhibited the NPY (10 nM)-induced increase in intracellular calcium levels (IC(50) = 3.2 nM) in cells expressing human Y(1) receptors. In contrast, J-104870 showed low affinities for human Y(2) (K(i) > 10 microM), Y(4) (K(i) > 10 microM), and Y(5) receptors (K(i) = 6 microM). In rat hypothalamic membranes, J-104870 also completely displaced the binding of [(125)I]1229U91, which is known to bind to the typical Y(1) receptor, with a high affinity (K(i) = 2.0 nM). Intracerebroventricular (ICV) injection of J-104870 (200 microg) significantly suppressed NPY (5 microg)-induced feeding in satiated Sprague-Dawley rats by 74%. Furthermore, ICV and oral administration of J-104870 (200 microg and 100 mg/kg, respectively) significantly suppressed spontaneous food intake in Zucker fatty rats. These findings suggested that J-104870 is a selective and potent nonpeptide Y(1) antagonist with oral bioavailability and brain penetrability. In addition, the anorexigenic effect of J-104870 clearly revealed the participation of the Y(1) receptor in NPY-mediated feeding regulation. The potent and orally active Y(1) antagonist J-104970 is a useful tool for elucidating the physiological roles of NPY in obesity.
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PMID:The novel neuropeptide Y Y(1) receptor antagonist J-104870: a potent feeding suppressant with oral bioavailability. 1058 Nov 70

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