* 162640

NEUROPEPTIDE Y; NPY


Alternative titles; symbols

Y NEUROPEPTIDE


HGNC Approved Gene Symbol: NPY

Cytogenetic location: 7p15.3     Genomic coordinates (GRCh38): 7:24,284,190-24,291,862 (from NCBI)


TEXT

Cloning and Expression

Neuropeptide Y (NPY) is an abundant and widespread peptide in the mammalian nervous system. It shows sequence homology to peptide YY and over 50% homology in amino acid and nucleotide sequence to pancreatic polypeptide (PNP; 167780). NPY is a 36-amino acid peptide. Minth et al. (1984) cloned the NPY gene starting from mRNA of a pheochromocytoma.

Takeuchi et al. (1985, 1986) isolated cDNA clones of the NPY and PNP genes from a pheochromocytoma and a pancreatic endocrine tumor, respectively.


Gene Function

Terenghi et al. (1987) determined the distribution of mRNA encoding NPY in neurons of the cerebral cortex in surgical biopsy specimens and postmortem brain by means of in situ hybridization techniques. They showed consistent localization of NPY gene transcription and expression in normal mature cortical neurons.

Hansel et al. (2001) identified a role for NPY in promoting proliferation of postnatal neuronal precursor cells. NPY is synthesized in the postnatal olfactory epithelium by sustentacular cells, previously proposed to function only in structural support. Mice with a targeted deletion of NPY contained half as many dividing olfactory neuronal precursor cells as did controls. Furthermore, NPY-deficient mice developed significantly fewer olfactory neurons by adulthood. NPY acts on multipotent neuronal precursor or basal cells to activate rapidly and transiently the extracellular signal-regulated kinase (ERK) 1/2 (601795) subgroup of mitogen-activated protein kinases. The NPY Y1 receptor subtype (162641) appears to mediate this effect. The ability of NPY to induce neuronal precursor proliferation is mediated by protein kinase C (PKC; 176960), indicating an upstream PKC-dependent activation of ERK1/2. These results indicate that NPY may regulate neuronal precursor proliferation in the adult mammal.

NPY and proopiomelanocortin (POMC; 176830) neurons in the infundibular (arcuate) nucleus of the hypothalamus are part of a reciprocal circuit regulating reproduction and energy balance. Based on studies showing an age-related decrease in POMC mRNA, Escobar et al. (2004) hypothesized that NPY gene expression would increase in older women. Using in situ hybridization to compare NPY mRNA levels between young (premenopausal) and older (postmenopausal) women, they observed a significant increase (approximately 100%) in the numbers of autoradiographic grains per NPY neuron in the retrochiasmatic area and infundibular nucleus of older women. NPY mRNA was correlated with subject age and inversely proportional to the number of POMC neurons previously counted in the same subjects. The authors concluded that aging in women is associated with increased NPY gene expression and suggested that the functional relationship between NPY and POMC neurons demonstrated in other species also exists in the human.

Broqua et al. (1995) and Heilig et al. (1989) showed that neuropeptide Y is anxiolytic while Thorsell et al. (1999) showed that its release is induced by stress. Adrian et al. (1983) and Allen et al. (1983) showed that NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories. Zhou et al. (2008) showed that haplotype-driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY mRNA in postmortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype-driven NPY expression predicted a higher emotion-induced activation of the amygdala, as well as diminished resiliency as assessed by pain/stress-induced activations of endogenous opioid neurotransmission in various brain regions. A SNP, rs16147, located in the promoter region altered NPY expression in vitro and seemed to account for more than half of the variation in expression in vivo. Zhou et al. (2008) concluded that these convergent findings were consistent with the function of NPY as an anxiolytic peptide and helped to explain interindividual variation in resiliency to stress, a risk factor for many diseases.

Andrews et al. (2008) showed that ghrelin (605353) initiates robust changes in hypothalamic mitochondrial respiration in mice that are dependent on uncoupling protein-2 (UCP2; 601693). Activation of this mitochondrial mechanism is critical for ghrelin-induced mitochondrial proliferation and electric activation of NPY/AgRP (602311) neurons, for ghrelin-triggered synaptic plasticity of POMC neurons, and for ghrelin-induced food intake. The UCP2-dependent action of ghrelin on NPY/AgRP neurons is driven by a hypothalamic fatty acid oxidation pathway involving AMPK (see 602739), CPT1 (600528), and free radicals that are scavenged by UCP2. Andrews et al. (2008) concluded that their results revealed a signaling modality connecting mitochondria-mediated effects of G protein-coupled receptors on neuronal function and associated behavior.

Benarroch (2009) provided a review of the multiple effects of neuropeptide Y in the central nervous system and discussed its possible role in the modulation of cortical excitability, circadian rhythms, pain processing, stress response, neuroprotection, and neurogenesis, among others. Much of the information was compiled from animal studies.


Mapping

Using cDNA probes to analyze genomic DNA from chromosome assignment panels of human-mouse somatic cell hybrids, Takeuchi et al. (1985, 1986) examined whether the NPY and PNP genes are syntenic. The studies showed nonsynteny, with NPY on 7pter-7q22 and PNP on 17p11.1-17qter. By studies of a backcross with Mus spretus, Bahary et al. (1991) mapped the homologous NPY gene to mouse chromosome 6. Since mouse chromosome 6 has homology to human 7q, it is likely that the NPY gene in man is located in the region 7cen-q22.

Meisler et al. (1987) excluded close linkage between the loci for cystic fibrosis (219700) and neuropeptide Y.

Baker et al. (1995) showed by fluorescence in situ hybridization that the NPY gene is located on 7p15.1 and exists in single copy. They commented that NPY is one of the most highly conserved peptides known, with, for example, only 3 amino acid differences between human and shark.


Animal Model

Neuropeptide Y is a neuromodulator implicated in the control of energy balance and is overproduced in the hypothalamus of ob/ob mice. To determine the role of NPY in the response to leptin (164160) deficiency, Erickson et al. (1996) generated ob/ob mice deficient in NPY. In the absence of NPY, ob/ob mice were less obese because of reduced food intake and increased energy expenditure, and were less severely affected by diabetes, sterility, and somatotropic defects. These results were interpreted as indicating that NPY is a central effector of leptin deficiency.

Genetic linkage analysis of rats that were selectively bred for alcohol preference identified a chromosomal region that included the NPY gene (Carr et al., 1998). Alcohol-preferring rats had lower levels of NPY in several brain regions compared with alcohol-nonpreferring rats. Thiele et al. (1998) therefore studied alcohol consumption by mice that completely lacked NPY as a result of targeted gene disruption (Erickson et al., 1996). They found that NPY-deficient mice showed increased consumption, compared with wildtype mice, of solutions containing 6%, 10%, and 20% (by volume) ethanol. NPY-deficient mice were also less sensitive to the sedative/hypnotic effects of ethanol, as shown by more rapid recovery from ethanol-induced sleep, even though plasma ethanol concentrations did not differ significantly from those of controls. In contrast, transgenic mice that overexpressed a labeled NPY gene in neurons that usually express it had a lower preference for ethanol and were more sensitive to the sedative/hypnotic effects of ethanol than controls. These data provided direct evidence that alcohol consumption and resistance are inversely related to NPY levels in the brain.

Using the mouse corneal micropocket and the chick chorioallantoic membrane assays, Ekstrand et al. (2003) found that NPY acts as a potent angiogenic factor in vivo. Unlike vascular endothelial growth factor (VEGF; 192240), microvessels induced by NPY had distinct vascular tree-like structures showing vasodilation. This angiogenic pattern was similar to that induced by fibroblast growth factor-2 (FGF2; 134920), and the angiogenic response was dose-dependent. In knockout mice lacking the NPY Y2 receptor (162642), skin wound repair was significantly delayed. This study demonstrated that NPY may play an important role in regulation of angiogenesis and angiogenesis-dependent physiologic and pathologic processes.

In a rat ischemic hindlimb model, Lee et al. (2003) observed stimulation of sympathetic NPY release (attenuated by lumbar sympathectomy) and upregulation of NPY-Y2 receptor and a peptidase forming Y2/Y5 (602001)-selective agonist. Exogenous NPY at physiologic concentrations also induced Y5 receptor, stimulated neovascularization, and restored ischemic muscle blood flow and performance. Ex vivo NPY-mediated aortic sprouting was blocked by an antibody neutralizing a VEGF receptor, fetal liver kinase-1 (191306), and abolished in mice null for eNOS (NOS3; 163729). Lee et al. (2003) concluded that NPY mediates neurogenic ischemic angiogenesis at physiologic concentrations by activating Y2/Y5 receptors and eNOS, in part due to release of VEGF.

To determine whether neurons that express NPY and agouti-related protein (602311) are essential in mice, Luquet et al. (2005) targeted the human diphtheria toxin receptor (126150) to the Agrp locus, which allows temporally controlled ablation of Npy/Agrp neurons to occur after an injection of diphtheria toxin. Neonatal ablation of Npy/Agrp neurons had minimal effects on feeding, whereas their ablation in adults caused rapid starvation. Luquet et al. (2005) concluded that network-based compensatory mechanisms can develop after the ablation of Npy/Agrp neurons in neonates but do not readily occur when these neurons become essential in adults.

In mice, Kuo et al. (2007) showed that stress exaggerates diet-induced obesity through a peripheral mechanism in the abdominal white adipose tissue that is mediated by neuropeptide Y. Stressors such as exposure to cold or aggression led to the release of NPY from sympathetic nerves, which in turn upregulated NPY and its Y2 receptors in a glucocorticoid-dependent manner in the abdominal fat. This positive feedback response by NPY led to the growth of abdominal fat. Release of NPY and activation of NPY2R stimulated fat angiogenesis, macrophage infiltration, and the proliferation and differentiation of new adipocytes, resulting in abdominal obesity and a metabolic syndrome-like condition. Kuo et al. (2007) concluded that NPY, like stress, stimulates mouse and human fat growth, whereas pharmacologic inhibition or fat-targeted knockdown of NPY2R is antiangiogenic and antiadipogenic, while reducing abdominal obesity and metabolic abnormalities.

Reddy et al. (2009) investigated natural variation in C. elegans resistance to pathogen infection. With the use of quantitative genetic analysis, they determined that the pathogen susceptibility difference between the laboratory wildtype strain N2 and the wild isolate CB4856 is caused by a polymorphism in the npr1 gene, which encodes a homolog of the mammalian neuropeptide Y receptor. Reddy et al. (2009) showed that the mechanism of NPR1-mediated pathogen resistance is through oxygen-dependent behavioral avoidance rather than direct regulation of innate immunity. For C. elegans, bacteria represent food but also a potential source of infection. Reddy et al. (2009) concluded that their data underscored the importance of behavioral responses to oxygen levels in finding an optimal balance between these potentially conflicting cues.

Padilla et al. (2010) used BrdU labeling of mouse embryos in utero to show that Pomc (176830) was first expressed in neuronal cells in the hypothalamic ventricular zone at embryonic day (E) 10.5-E11.5. Expression of Npy first appeared in laterally situated cells at E13.5, with subsequent expression in the ventromedial arcuate nucleus of the hypothalamus (ARH). Some cells showed coexpression of these genes at midgestation, whereas adult cell populations showed mutually exclusive expression. Further studies indicated that about half of embryonic Pomc-expressing precursors subsequently adopted a non-Pomc fate in adult mice, and that nearly one-quarter of the mature Npy-positive cells shared a common progenitor with Pomc-positive cells. These findings were consistent with the hypothesis that cell fate decisions may be influenced by factors during gestation. Importantly, the 2 best-characterized ARH populations, neurons that express orexigenic NPY and neurons that express anorexigenic POMC, produce antagonistic effects on food intake and energy homeostasis, which may have implications for body weight and obesity.


ALLELIC VARIANTS ( 1 Selected Example):

.0001 NEUROPEPTIDE Y POLYMORPHISM

NPY, LEU7PRO
  
RCV000015068...

As part of an ongoing study of the genetic basis of obesity, Karvonen et al. (1998) identified a 1128T-C polymorphism that resulted in substitution of leucine by proline at residue 7 (L7P) in the signal peptide part of pre-pro-NPY. This polymorphism was not associated with obesity or energy metabolism, but was significantly and consistently associated with high serum total and LDL cholesterol levels both in normal-weight and obese Finns and in obese Dutch subjects. Uusitupa et al. (1998) found the pro7 polymorphism in 14% of Finns but in only 6% of Dutchmen. Subjects with pro7 in NPY had, on average, 0.6 to 1.4 mmol/L higher serum total cholesterol levels than those without this gene variant. As the impact of pro7 NPY on serum cholesterol levels could not be found in normal-weight Dutchmen, it can be assumed that obese persons may be more susceptible to the effect of the gene variant. It was calculated that the probability of having the pro7 in NPY could be as high as 50 to 60% in obese subjects with a total serum cholesterol equal to or higher than 8 mmol/L. At least among Finns, the pro7 form of NPY is one of the strongest genetic factors affecting serum cholesterol levels.

Karvonen et al. (2000) investigated whether the leu7-to-pro NPY polymorphism is associated with birth weight. The study comprised 688 children participating in the Special Turku Coronary Risk Factor Intervention Project. The pro7 polymorphism was constantly associated with 14 to 17% higher mean serum triglyceride values in boys at the ages of 5 and 7 years (P = 0.023). In addition, boys with the pro7 allele had, on the average, a 193-g higher birth weight than boys homozygous for the leu7 allele (P = 0.03). The authors concluded that the leu7-to-pro polymorphism may thus be linked with serum triglyceride concentrations, but not with serum cholesterol concentrations, in gender-specific manner in preschoolers.

Kauhanen et al. (2000) analyzed 889 middle-aged men from eastern Finland for the leu7-to-pro polymorphism of NPY. The gene variant producing the pro7 substitution was associated with a 34% higher average alcohol consumption, even after adjustment for a number of covariates. The proportion of heavy drinkers was also higher in this group (13.1% vs 8.2%, P = 0.10). The authors suggested that alcohol preference in humans may be regulated by the NPY system.

Lappalainen et al. (2002) studied 2 independently collected samples of European American alcohol-dependent subjects (307 subjects in sample 1; 160 subjects in sample 2) and a sample of psychiatrically screened European American controls (202 subjects); 8 population samples, including African Americans and European Americans (551 subjects); and 4 samples of individuals with Alzheimer disease, schizophrenia, posttraumatic stress disorder, and major depression (502 subjects). L7P allele frequencies were determined between alcohol-dependent subjects and controls. The frequency of the pro7 allele was higher in alcohol-dependent subjects (5.5% in sample 1 and 5.0% in sample 2) compared with screened European American controls (2.0%) (sample 1 vs control, P = 0.006; sample 2 vs control, P = 0.03). The attributable fraction (excess morbidity) owing to the pro7 allele was estimated to be 7.3%. There was no evidence that the association of the pro7 allele with alcohol dependence was due to association with a comorbid psychiatric disorder. Lappalainen et al. (2002) suggested that the NPY pro7 allele is a risk factor for alcohol dependence.

Niskanen et al. (2000) investigated the association of the L7P polymorphism with common carotid intima media thickness (IMT), assessed by ultrasonograph, in 81 patients with type II diabetes (41 men and 40 women; mean age, 67.1 years) and in 105 nondiabetic subjects (48 men and 57 women; mean age, 65.5 years) and genotyped for the L7P polymorphism in prepro-NPY. The frequency of pro7 in prepro-NPY was 9.9% in the diabetic patients and 14.3% in the control subjects (P of 0.360). In the analysis of covariance of the entire group, the mean common carotid IMT was independently associated with the L7P polymorphism (F of 5.165; P of 0.024) after adjustment for known risk factors. The authors concluded that the presence of the pro7 substitution in the prepro-NPY associates with increased carotid atherosclerosis.

Kallio et al. (2003) elucidated the role of the L7P polymorphism (rs16139) in diurnal cardiovascular, metabolic, and hormonal functions of healthy subjects during rest. Subjects with the L7P polymorphism had significantly lower plasma NPY and norepinephrine concentrations, lower insulin concentrations, higher glucose concentrations, and lower insulin-glucose ratio in plasma than the controls. Heart rate was significantly higher during daytime in the subjects with L7P polymorphism. The authors concluded that genetically determined changes in NPY levels lead to widespread consequences in the control of sympathoadrenal, metabolic, and hormonal balance in healthy subjects.


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Cassandra L. Kniffin - updated : 5/27/2010
Cassandra L. Kniffin - updated : 1/13/2010
Ada Hamosh - updated : 6/16/2009
Ada Hamosh - updated : 3/12/2009
Ada Hamosh - updated : 9/3/2008
Ada Hamosh - updated : 5/23/2008
Ada Hamosh - updated : 2/25/2008
Ada Hamosh - updated : 11/14/2005
John A. Phillips, III - updated : 7/26/2005
Marla J. F. O'Neill - updated : 3/17/2005
John A. Phillips, III - updated : 8/2/2004
Victor A. McKusick - updated : 6/19/2003
John Logan Black, III - updated : 11/15/2002
John A. Phillips, III - updated : 5/10/2001
Ada Hamosh - updated : 4/17/2001
John A. Phillips, III - updated : 11/16/2000
Sonja A. Rasmussen - updated : 9/15/2000
Victor A. McKusick - updated : 3/22/1999
Victor A. McKusick - updated : 11/23/1998
Creation Date:
Victor A. McKusick : 6/2/1986
carol : 11/20/2019
carol : 08/22/2016
terry : 10/10/2012
terry : 9/14/2012
wwang : 6/15/2010
ckniffin : 5/27/2010
wwang : 5/6/2010
wwang : 1/27/2010
ckniffin : 1/13/2010
terry : 12/16/2009
alopez : 7/16/2009
terry : 6/16/2009
alopez : 3/20/2009
terry : 3/12/2009
alopez : 9/12/2008
terry : 9/3/2008
carol : 7/8/2008
alopez : 6/3/2008
terry : 5/23/2008
alopez : 3/3/2008
terry : 2/25/2008
terry : 11/15/2006
alopez : 11/15/2005
terry : 11/14/2005
alopez : 7/26/2005
wwang : 3/17/2005
alopez : 8/2/2004
terry : 8/15/2003
alopez : 6/26/2003
terry : 6/19/2003
carol : 11/15/2002
mgross : 5/10/2001
terry : 5/10/2001
alopez : 4/18/2001
terry : 4/17/2001
terry : 1/24/2001
alopez : 1/24/2001
terry : 11/16/2000
mcapotos : 9/22/2000
mcapotos : 9/15/2000
carol : 3/23/1999
terry : 3/23/1999
terry : 3/22/1999
dkim : 12/2/1998
alopez : 11/25/1998
terry : 11/23/1998
mark : 12/9/1996
terry : 12/6/1996
terry : 4/14/1995
carol : 11/12/1993
supermim : 3/16/1992
carol : 9/6/1991
supermim : 3/20/1990
supermim : 3/9/1990

* 162640

NEUROPEPTIDE Y; NPY


Alternative titles; symbols

Y NEUROPEPTIDE


HGNC Approved Gene Symbol: NPY

Cytogenetic location: 7p15.3     Genomic coordinates (GRCh38): 7:24,284,190-24,291,862 (from NCBI)


TEXT

Cloning and Expression

Neuropeptide Y (NPY) is an abundant and widespread peptide in the mammalian nervous system. It shows sequence homology to peptide YY and over 50% homology in amino acid and nucleotide sequence to pancreatic polypeptide (PNP; 167780). NPY is a 36-amino acid peptide. Minth et al. (1984) cloned the NPY gene starting from mRNA of a pheochromocytoma.

Takeuchi et al. (1985, 1986) isolated cDNA clones of the NPY and PNP genes from a pheochromocytoma and a pancreatic endocrine tumor, respectively.


Gene Function

Terenghi et al. (1987) determined the distribution of mRNA encoding NPY in neurons of the cerebral cortex in surgical biopsy specimens and postmortem brain by means of in situ hybridization techniques. They showed consistent localization of NPY gene transcription and expression in normal mature cortical neurons.

Hansel et al. (2001) identified a role for NPY in promoting proliferation of postnatal neuronal precursor cells. NPY is synthesized in the postnatal olfactory epithelium by sustentacular cells, previously proposed to function only in structural support. Mice with a targeted deletion of NPY contained half as many dividing olfactory neuronal precursor cells as did controls. Furthermore, NPY-deficient mice developed significantly fewer olfactory neurons by adulthood. NPY acts on multipotent neuronal precursor or basal cells to activate rapidly and transiently the extracellular signal-regulated kinase (ERK) 1/2 (601795) subgroup of mitogen-activated protein kinases. The NPY Y1 receptor subtype (162641) appears to mediate this effect. The ability of NPY to induce neuronal precursor proliferation is mediated by protein kinase C (PKC; 176960), indicating an upstream PKC-dependent activation of ERK1/2. These results indicate that NPY may regulate neuronal precursor proliferation in the adult mammal.

NPY and proopiomelanocortin (POMC; 176830) neurons in the infundibular (arcuate) nucleus of the hypothalamus are part of a reciprocal circuit regulating reproduction and energy balance. Based on studies showing an age-related decrease in POMC mRNA, Escobar et al. (2004) hypothesized that NPY gene expression would increase in older women. Using in situ hybridization to compare NPY mRNA levels between young (premenopausal) and older (postmenopausal) women, they observed a significant increase (approximately 100%) in the numbers of autoradiographic grains per NPY neuron in the retrochiasmatic area and infundibular nucleus of older women. NPY mRNA was correlated with subject age and inversely proportional to the number of POMC neurons previously counted in the same subjects. The authors concluded that aging in women is associated with increased NPY gene expression and suggested that the functional relationship between NPY and POMC neurons demonstrated in other species also exists in the human.

Broqua et al. (1995) and Heilig et al. (1989) showed that neuropeptide Y is anxiolytic while Thorsell et al. (1999) showed that its release is induced by stress. Adrian et al. (1983) and Allen et al. (1983) showed that NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories. Zhou et al. (2008) showed that haplotype-driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY mRNA in postmortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype-driven NPY expression predicted a higher emotion-induced activation of the amygdala, as well as diminished resiliency as assessed by pain/stress-induced activations of endogenous opioid neurotransmission in various brain regions. A SNP, rs16147, located in the promoter region altered NPY expression in vitro and seemed to account for more than half of the variation in expression in vivo. Zhou et al. (2008) concluded that these convergent findings were consistent with the function of NPY as an anxiolytic peptide and helped to explain interindividual variation in resiliency to stress, a risk factor for many diseases.

Andrews et al. (2008) showed that ghrelin (605353) initiates robust changes in hypothalamic mitochondrial respiration in mice that are dependent on uncoupling protein-2 (UCP2; 601693). Activation of this mitochondrial mechanism is critical for ghrelin-induced mitochondrial proliferation and electric activation of NPY/AgRP (602311) neurons, for ghrelin-triggered synaptic plasticity of POMC neurons, and for ghrelin-induced food intake. The UCP2-dependent action of ghrelin on NPY/AgRP neurons is driven by a hypothalamic fatty acid oxidation pathway involving AMPK (see 602739), CPT1 (600528), and free radicals that are scavenged by UCP2. Andrews et al. (2008) concluded that their results revealed a signaling modality connecting mitochondria-mediated effects of G protein-coupled receptors on neuronal function and associated behavior.

Benarroch (2009) provided a review of the multiple effects of neuropeptide Y in the central nervous system and discussed its possible role in the modulation of cortical excitability, circadian rhythms, pain processing, stress response, neuroprotection, and neurogenesis, among others. Much of the information was compiled from animal studies.


Mapping

Using cDNA probes to analyze genomic DNA from chromosome assignment panels of human-mouse somatic cell hybrids, Takeuchi et al. (1985, 1986) examined whether the NPY and PNP genes are syntenic. The studies showed nonsynteny, with NPY on 7pter-7q22 and PNP on 17p11.1-17qter. By studies of a backcross with Mus spretus, Bahary et al. (1991) mapped the homologous NPY gene to mouse chromosome 6. Since mouse chromosome 6 has homology to human 7q, it is likely that the NPY gene in man is located in the region 7cen-q22.

Meisler et al. (1987) excluded close linkage between the loci for cystic fibrosis (219700) and neuropeptide Y.

Baker et al. (1995) showed by fluorescence in situ hybridization that the NPY gene is located on 7p15.1 and exists in single copy. They commented that NPY is one of the most highly conserved peptides known, with, for example, only 3 amino acid differences between human and shark.


Animal Model

Neuropeptide Y is a neuromodulator implicated in the control of energy balance and is overproduced in the hypothalamus of ob/ob mice. To determine the role of NPY in the response to leptin (164160) deficiency, Erickson et al. (1996) generated ob/ob mice deficient in NPY. In the absence of NPY, ob/ob mice were less obese because of reduced food intake and increased energy expenditure, and were less severely affected by diabetes, sterility, and somatotropic defects. These results were interpreted as indicating that NPY is a central effector of leptin deficiency.

Genetic linkage analysis of rats that were selectively bred for alcohol preference identified a chromosomal region that included the NPY gene (Carr et al., 1998). Alcohol-preferring rats had lower levels of NPY in several brain regions compared with alcohol-nonpreferring rats. Thiele et al. (1998) therefore studied alcohol consumption by mice that completely lacked NPY as a result of targeted gene disruption (Erickson et al., 1996). They found that NPY-deficient mice showed increased consumption, compared with wildtype mice, of solutions containing 6%, 10%, and 20% (by volume) ethanol. NPY-deficient mice were also less sensitive to the sedative/hypnotic effects of ethanol, as shown by more rapid recovery from ethanol-induced sleep, even though plasma ethanol concentrations did not differ significantly from those of controls. In contrast, transgenic mice that overexpressed a labeled NPY gene in neurons that usually express it had a lower preference for ethanol and were more sensitive to the sedative/hypnotic effects of ethanol than controls. These data provided direct evidence that alcohol consumption and resistance are inversely related to NPY levels in the brain.

Using the mouse corneal micropocket and the chick chorioallantoic membrane assays, Ekstrand et al. (2003) found that NPY acts as a potent angiogenic factor in vivo. Unlike vascular endothelial growth factor (VEGF; 192240), microvessels induced by NPY had distinct vascular tree-like structures showing vasodilation. This angiogenic pattern was similar to that induced by fibroblast growth factor-2 (FGF2; 134920), and the angiogenic response was dose-dependent. In knockout mice lacking the NPY Y2 receptor (162642), skin wound repair was significantly delayed. This study demonstrated that NPY may play an important role in regulation of angiogenesis and angiogenesis-dependent physiologic and pathologic processes.

In a rat ischemic hindlimb model, Lee et al. (2003) observed stimulation of sympathetic NPY release (attenuated by lumbar sympathectomy) and upregulation of NPY-Y2 receptor and a peptidase forming Y2/Y5 (602001)-selective agonist. Exogenous NPY at physiologic concentrations also induced Y5 receptor, stimulated neovascularization, and restored ischemic muscle blood flow and performance. Ex vivo NPY-mediated aortic sprouting was blocked by an antibody neutralizing a VEGF receptor, fetal liver kinase-1 (191306), and abolished in mice null for eNOS (NOS3; 163729). Lee et al. (2003) concluded that NPY mediates neurogenic ischemic angiogenesis at physiologic concentrations by activating Y2/Y5 receptors and eNOS, in part due to release of VEGF.

To determine whether neurons that express NPY and agouti-related protein (602311) are essential in mice, Luquet et al. (2005) targeted the human diphtheria toxin receptor (126150) to the Agrp locus, which allows temporally controlled ablation of Npy/Agrp neurons to occur after an injection of diphtheria toxin. Neonatal ablation of Npy/Agrp neurons had minimal effects on feeding, whereas their ablation in adults caused rapid starvation. Luquet et al. (2005) concluded that network-based compensatory mechanisms can develop after the ablation of Npy/Agrp neurons in neonates but do not readily occur when these neurons become essential in adults.

In mice, Kuo et al. (2007) showed that stress exaggerates diet-induced obesity through a peripheral mechanism in the abdominal white adipose tissue that is mediated by neuropeptide Y. Stressors such as exposure to cold or aggression led to the release of NPY from sympathetic nerves, which in turn upregulated NPY and its Y2 receptors in a glucocorticoid-dependent manner in the abdominal fat. This positive feedback response by NPY led to the growth of abdominal fat. Release of NPY and activation of NPY2R stimulated fat angiogenesis, macrophage infiltration, and the proliferation and differentiation of new adipocytes, resulting in abdominal obesity and a metabolic syndrome-like condition. Kuo et al. (2007) concluded that NPY, like stress, stimulates mouse and human fat growth, whereas pharmacologic inhibition or fat-targeted knockdown of NPY2R is antiangiogenic and antiadipogenic, while reducing abdominal obesity and metabolic abnormalities.

Reddy et al. (2009) investigated natural variation in C. elegans resistance to pathogen infection. With the use of quantitative genetic analysis, they determined that the pathogen susceptibility difference between the laboratory wildtype strain N2 and the wild isolate CB4856 is caused by a polymorphism in the npr1 gene, which encodes a homolog of the mammalian neuropeptide Y receptor. Reddy et al. (2009) showed that the mechanism of NPR1-mediated pathogen resistance is through oxygen-dependent behavioral avoidance rather than direct regulation of innate immunity. For C. elegans, bacteria represent food but also a potential source of infection. Reddy et al. (2009) concluded that their data underscored the importance of behavioral responses to oxygen levels in finding an optimal balance between these potentially conflicting cues.

Padilla et al. (2010) used BrdU labeling of mouse embryos in utero to show that Pomc (176830) was first expressed in neuronal cells in the hypothalamic ventricular zone at embryonic day (E) 10.5-E11.5. Expression of Npy first appeared in laterally situated cells at E13.5, with subsequent expression in the ventromedial arcuate nucleus of the hypothalamus (ARH). Some cells showed coexpression of these genes at midgestation, whereas adult cell populations showed mutually exclusive expression. Further studies indicated that about half of embryonic Pomc-expressing precursors subsequently adopted a non-Pomc fate in adult mice, and that nearly one-quarter of the mature Npy-positive cells shared a common progenitor with Pomc-positive cells. These findings were consistent with the hypothesis that cell fate decisions may be influenced by factors during gestation. Importantly, the 2 best-characterized ARH populations, neurons that express orexigenic NPY and neurons that express anorexigenic POMC, produce antagonistic effects on food intake and energy homeostasis, which may have implications for body weight and obesity.


ALLELIC VARIANTS 1 Selected Example):

.0001   NEUROPEPTIDE Y POLYMORPHISM

NPY, LEU7PRO
SNP: rs16139, gnomAD: rs16139, ClinVar: RCV000015068, RCV002054440

As part of an ongoing study of the genetic basis of obesity, Karvonen et al. (1998) identified a 1128T-C polymorphism that resulted in substitution of leucine by proline at residue 7 (L7P) in the signal peptide part of pre-pro-NPY. This polymorphism was not associated with obesity or energy metabolism, but was significantly and consistently associated with high serum total and LDL cholesterol levels both in normal-weight and obese Finns and in obese Dutch subjects. Uusitupa et al. (1998) found the pro7 polymorphism in 14% of Finns but in only 6% of Dutchmen. Subjects with pro7 in NPY had, on average, 0.6 to 1.4 mmol/L higher serum total cholesterol levels than those without this gene variant. As the impact of pro7 NPY on serum cholesterol levels could not be found in normal-weight Dutchmen, it can be assumed that obese persons may be more susceptible to the effect of the gene variant. It was calculated that the probability of having the pro7 in NPY could be as high as 50 to 60% in obese subjects with a total serum cholesterol equal to or higher than 8 mmol/L. At least among Finns, the pro7 form of NPY is one of the strongest genetic factors affecting serum cholesterol levels.

Karvonen et al. (2000) investigated whether the leu7-to-pro NPY polymorphism is associated with birth weight. The study comprised 688 children participating in the Special Turku Coronary Risk Factor Intervention Project. The pro7 polymorphism was constantly associated with 14 to 17% higher mean serum triglyceride values in boys at the ages of 5 and 7 years (P = 0.023). In addition, boys with the pro7 allele had, on the average, a 193-g higher birth weight than boys homozygous for the leu7 allele (P = 0.03). The authors concluded that the leu7-to-pro polymorphism may thus be linked with serum triglyceride concentrations, but not with serum cholesterol concentrations, in gender-specific manner in preschoolers.

Kauhanen et al. (2000) analyzed 889 middle-aged men from eastern Finland for the leu7-to-pro polymorphism of NPY. The gene variant producing the pro7 substitution was associated with a 34% higher average alcohol consumption, even after adjustment for a number of covariates. The proportion of heavy drinkers was also higher in this group (13.1% vs 8.2%, P = 0.10). The authors suggested that alcohol preference in humans may be regulated by the NPY system.

Lappalainen et al. (2002) studied 2 independently collected samples of European American alcohol-dependent subjects (307 subjects in sample 1; 160 subjects in sample 2) and a sample of psychiatrically screened European American controls (202 subjects); 8 population samples, including African Americans and European Americans (551 subjects); and 4 samples of individuals with Alzheimer disease, schizophrenia, posttraumatic stress disorder, and major depression (502 subjects). L7P allele frequencies were determined between alcohol-dependent subjects and controls. The frequency of the pro7 allele was higher in alcohol-dependent subjects (5.5% in sample 1 and 5.0% in sample 2) compared with screened European American controls (2.0%) (sample 1 vs control, P = 0.006; sample 2 vs control, P = 0.03). The attributable fraction (excess morbidity) owing to the pro7 allele was estimated to be 7.3%. There was no evidence that the association of the pro7 allele with alcohol dependence was due to association with a comorbid psychiatric disorder. Lappalainen et al. (2002) suggested that the NPY pro7 allele is a risk factor for alcohol dependence.

Niskanen et al. (2000) investigated the association of the L7P polymorphism with common carotid intima media thickness (IMT), assessed by ultrasonograph, in 81 patients with type II diabetes (41 men and 40 women; mean age, 67.1 years) and in 105 nondiabetic subjects (48 men and 57 women; mean age, 65.5 years) and genotyped for the L7P polymorphism in prepro-NPY. The frequency of pro7 in prepro-NPY was 9.9% in the diabetic patients and 14.3% in the control subjects (P of 0.360). In the analysis of covariance of the entire group, the mean common carotid IMT was independently associated with the L7P polymorphism (F of 5.165; P of 0.024) after adjustment for known risk factors. The authors concluded that the presence of the pro7 substitution in the prepro-NPY associates with increased carotid atherosclerosis.

Kallio et al. (2003) elucidated the role of the L7P polymorphism (rs16139) in diurnal cardiovascular, metabolic, and hormonal functions of healthy subjects during rest. Subjects with the L7P polymorphism had significantly lower plasma NPY and norepinephrine concentrations, lower insulin concentrations, higher glucose concentrations, and lower insulin-glucose ratio in plasma than the controls. Heart rate was significantly higher during daytime in the subjects with L7P polymorphism. The authors concluded that genetically determined changes in NPY levels lead to widespread consequences in the control of sympathoadrenal, metabolic, and hormonal balance in healthy subjects.


See Also:

Allen and Bloom (1986); Dockray (1986); Maccarrone and Jarrott (1986); Minth et al. (1986)

REFERENCES

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Contributors:
Cassandra L. Kniffin - updated : 5/27/2010
Cassandra L. Kniffin - updated : 1/13/2010
Ada Hamosh - updated : 6/16/2009
Ada Hamosh - updated : 3/12/2009
Ada Hamosh - updated : 9/3/2008
Ada Hamosh - updated : 5/23/2008
Ada Hamosh - updated : 2/25/2008
Ada Hamosh - updated : 11/14/2005
John A. Phillips, III - updated : 7/26/2005
Marla J. F. O'Neill - updated : 3/17/2005
John A. Phillips, III - updated : 8/2/2004
Victor A. McKusick - updated : 6/19/2003
John Logan Black, III - updated : 11/15/2002
John A. Phillips, III - updated : 5/10/2001
Ada Hamosh - updated : 4/17/2001
John A. Phillips, III - updated : 11/16/2000
Sonja A. Rasmussen - updated : 9/15/2000
Victor A. McKusick - updated : 3/22/1999
Victor A. McKusick - updated : 11/23/1998

Creation Date:
Victor A. McKusick : 6/2/1986

Edit History:
carol : 11/20/2019
carol : 08/22/2016
terry : 10/10/2012
terry : 9/14/2012
wwang : 6/15/2010
ckniffin : 5/27/2010
wwang : 5/6/2010
wwang : 1/27/2010
ckniffin : 1/13/2010
terry : 12/16/2009
alopez : 7/16/2009
terry : 6/16/2009
alopez : 3/20/2009
terry : 3/12/2009
alopez : 9/12/2008
terry : 9/3/2008
carol : 7/8/2008
alopez : 6/3/2008
terry : 5/23/2008
alopez : 3/3/2008
terry : 2/25/2008
terry : 11/15/2006
alopez : 11/15/2005
terry : 11/14/2005
alopez : 7/26/2005
wwang : 3/17/2005
alopez : 8/2/2004
terry : 8/15/2003
alopez : 6/26/2003
terry : 6/19/2003
carol : 11/15/2002
mgross : 5/10/2001
terry : 5/10/2001
alopez : 4/18/2001
terry : 4/17/2001
terry : 1/24/2001
alopez : 1/24/2001
terry : 11/16/2000
mcapotos : 9/22/2000
mcapotos : 9/15/2000
carol : 3/23/1999
terry : 3/23/1999
terry : 3/22/1999
dkim : 12/2/1998
alopez : 11/25/1998
terry : 11/23/1998
mark : 12/9/1996
terry : 12/6/1996
terry : 4/14/1995
carol : 11/12/1993
supermim : 3/16/1992
carol : 9/6/1991
supermim : 3/20/1990
supermim : 3/9/1990