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Synthesis and release of neuropeptide Y (NPY) are both regulated by leptin binding to its hypothalamic receptor mediating some of the effects of leptin on food intake. Moreover, NPY administration is a powerful stimulant of feeding behaviour. Thus, we investigated the potential implication of NPY, NPY-Y1 and -Y5 subtype receptors [rNPY-Y1/-Y5] in t...
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... has been mapped at the same locus [17], with an estimated distance less than 2 Mb be- tween rNPY-Y5 and the marker D4S393. In our fam- ilies, three microsatellite markers (D4S413; D4S1588 and D4S393) flanking the rNPY-Y1/Y5 region were ordered with the LINKAGE program [28] as shown in Figure 2. ...
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Objective:
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... One of them is Neuropeptide Y (NPY) gene, which is localized on chromosome 7 (7p15.1) (ROCHE et al., 1997). and spans 14,678 kb region (NCBI Reference Sequence: NG_016148.1). ...
... Association between NPY gene variants and obesity and certain obesity-related phenotypes have been studied in many populations and different findings were obtained. Two studies carried out by Roche et al. in French morbidly obese cases and Bhaskar et al. in Indian population have found no evidence supporting the association (ROCHE et al., 1997;BHASKAR et al., 2010). In another study carried out in a population from Brasil have observed that NPY Leu7Pro variant was accounted for the decrease in BMI in premenapousal women (MATTEVİ et al., 2002). ...
... DISCUSSION Association of NPY gene Leu7Pro polymorphism with obesity has been studied in many populations and conflicting results were obtained. Several studies found no association with obesity results (ROCHE et al., 1997;BHASKAR et al., 2010;DING et al., 2003;KARVONEN et al., 1998), while several others found association but with different aspects of obesity. In a study Pro7 allele has been associated with lower BMI values as well as lower WHRs in women respectively (MATTEVİ et al.,2002;MUTSCHLER et al., 2013), while in another two studies it was associated with increased BMI values (van ROSSUM et al., 2006;DING et al., 2005) and increased risk of obesity (YEUNG et al., 2011). ...
Obesity, an important public health issue, is a risk factor for many diseases
and has been associated with many genes. The aim of this study was to
investigate if there is an association between an NPY gene polymorphism,
Leu7Pro, and obesity and/or obesity-related phenotypes. A total of 84 obese
cases (45 female and 39 male) and a total of 77 non-obese control subjects
(38 female and 39 male) were included in this case-control study. Body
weight and height measurements were used for calculation of Body Mass Index
(BMI) and the ones in the ranges of 18 to 25 kg/m2 were considered normal
and the ones 30 kg/m2 and over were considered obese from the subjects.
Minor allele frequency for Leu7Pro polymorphism was 3.5% and it was found to
be associated to increased obesity in the population studied. No significant
differences were observed between genotype distrubutions and allele
frequencies for both obese and non-obese subjects. However, mean BMI values
were found to be higher (38,88 ± 2,96) in obese cases having Pro7 allele
than non carriers of this allele (35,37 ± 5,16), (p=0.044). This is the
first study in a Turkey population which supports the role of Leu7Pro
polymorphism in obesity. Further studies with larger sample sizes may
confirm these findings and can contribute and shed light on the genetic
factors playing a part in Turkey population.
... In contrast, a novel polymorphism in the intervening segment between exons of the genes encoding NPY1-R and NPY5-R was associated with reduced serum triglyceride (TG) levels and HDL-cholesterol in a severely obese cohort [102] that should be considered as a protective lipid profile. Roche et al. [103] investigated the potential implication of NPY, NPY-Y1 and -Y5 subtype receptors [rNPY-Y1/-Y5] in the development of human obesity. Two complementary genetic approaches were used: 1) linkage analyses between obesity and polymorphic markers located nearby NPY and rNPY-Y1/-Y5 genes in 93 French Caucasian morbidly obese families; 2) single strand conformation polymorphism (SSCP) scanning of the coding region of the NPY and rNPYY1 genes performed in 50 unrelated obese patients ascertained. ...
... Moreover, SSCP scanning revealed no mutation in the coding region of NPY and rNPY-Y1 genes among obese subjects. The authors suggest that NPY and NPY-Y1/ Y5 receptors are unlikely to be implicated in the development of human morbid obesity, at least in the French Caucasian population [103]. ...
... It has also been reported that stress exaggerates diet-induced obesity through a peripheral mechanism in the abdominal white adipose tissue that is mediated by NPY (neuropeptide Y) [51]. Actually, synthesis and release of NPY are both regulated by leptin binding to its hypothalamic receptor which mediates some of the effects of leptin on food intake [51,52]. Another susceptible gene is NPY2R, a 5′ variant of which has been reported to be associated with both severe adult obesity and childhood obesity by case-control studies [52,53]. ...
... Actually, synthesis and release of NPY are both regulated by leptin binding to its hypothalamic receptor which mediates some of the effects of leptin on food intake [51,52]. Another susceptible gene is NPY2R, a 5′ variant of which has been reported to be associated with both severe adult obesity and childhood obesity by case-control studies [52,53]. Further, we examined gene function enrichment among the top 100 obesity-related genes by using DAVID to analyze enrichment of GO biological process terms. ...
The identification of genes involved in human complex diseases remains a great challenge in computational systems biology. Although methods have been developed to use disease phenotypic similarities with a protein-protein interaction network for the prioritization of candidate genes, other valuable omics data sources have been largely overlooked in these methods.
With this understanding, we proposed a method called BRIDGE to prioritize candidate genes by integrating disease phenotypic similarities with such omics data as protein-protein interactions, gene sequence similarities, gene expression patterns, gene ontology annotations, and gene pathway memberships. BRIDGE utilizes a multiple regression model with lasso penalty to automatically weight different data sources and is capable of discovering genes associated with diseases whose genetic bases are completely unknown.
We conducted large-scale cross-validation experiments and demonstrated that more than 60% known disease genes can be ranked top one by BRIDGE in simulated linkage intervals, suggesting the superior performance of this method. We further performed two comprehensive case studies by applying BRIDGE to predict novel genes and transcriptional networks involved in obesity and type II diabetes.
The proposed method provides an effective and scalable way for integrating multi omics data to infer disease genes. Further applications of BRIDGE will be benefit to providing novel disease genes and underlying mechanisms of human diseases.
... One of them is Neuropeptide Y (NPY) gene, which is localized on chromosome 7 (7p15.1) (ROCHE et al., 1997). and spans 14,678 kb region (NCBI Reference Sequence: NG_016148.1). ...
... Association between NPY gene variants and obesity and certain obesity-related phenotypes have been studied in many populations and different findings were obtained. Two studies carried out by Roche et al. in French morbidly obese cases and Bhaskar et al. in Indian population have found no evidence supporting the association (ROCHE et al., 1997;BHASKAR et al., 2010). In another study carried out in a population from Brasil have observed that NPY Leu7Pro variant was accounted for the decrease in BMI in premenapousal women (MATTEVİ et al., 2002). ...
... DISCUSSION Association of NPY gene Leu7Pro polymorphism with obesity has been studied in many populations and conflicting results were obtained. Several studies found no association with obesity results (ROCHE et al., 1997;BHASKAR et al., 2010;DING et al., 2003;KARVONEN et al., 1998), while several others found association but with different aspects of obesity. In a study Pro7 allele has been associated with lower BMI values as well as lower WHRs in women respectively (MATTEVİ et al.,2002;MUTSCHLER et al., 2013), while in another two studies it was associated with increased BMI values (van ROSSUM et al., 2006;DING et al., 2005) and increased risk of obesity (YEUNG et al., 2011). ...
... The NPY Y1 and Y5 receptors were investigated by genetic studies to identify a possible linkage between obesity and highly polymorphic markers in these genes. No linkage was found in a French Caucasian population, suggesting that these loci do not play a major role in human obesity [264]. Moreover, the attempt to detect genetic variants by single strand conformation polymorphism (SSCP) analysis was also negative. ...
The peptidic neuropeptide Y (NPY) has received great attention because it has been implicated in the regulation of several organ systems. In particular, NPY is involved in the regulatory loops that control food intake in the hypothalamus and appears also to be important for regulating the activity of neuroendocrine axes under poor metabolic conditions. Furthermore, NPY exerts vasoconstrictive action on the vasculature and potentiates the actions of many other vasoconstrictors. In addition, it was demonstrated to have trophic properties and could therefore contribute to cardiovascular remodeling. These various effects plus a number of others make NPY an attractive target for the potential treatment of human diseases, such as obesity, metabolic disorders, hypertension and heart failure.
... Supportive data in humans has been restricted to a neuroanatomical distribution similar to rodents (39,40) and to preliminary human genetic evidence in a very specific cohort (41). Indeed, other human genetic studies have resulted in negative findings (42,43). The data reported herein identify NPY5RA-972 as a potent and selective NPY Y5 receptor antagonist with good systemic and CNS exposure after oral dosing in rats, suggesting that it is a useful tool with which to explore the role(s) of NPY Y5 in physiological processes. ...
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.
... 94 The NPY cod, NPY Yb=zYb and NPY zYc receptors display NPY Y 1 -like pharmacology while the NPY zYa subtype seems to have a pharmacological profile closer to the NPY Y 5 receptor. 90 However, amino-acid sequence comparisons and phylogenetic analyses have shown that NPY zYb, zYc and zYa receptors are 101 and Glu-4-Ala (NPY Y 5 ) 104 nor the silent polymorphism Gly-426-Gly (NPY Y 5 ) 103 have associations with extremes of body weight. Conversely in a recent study, three novel single nucleotide polymorphisms (P1, P2 and P3) located in the NPY Y 5 receptor gene non-coding region had an association with extreme obesity in Pima Indians. ...
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.
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 Y2 and NPY Y5 receptors in the complex sequence of physiological and behavioral events that underlie the long-term control of appetite.
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.
... The importance of melanocortin pathways has been suggested by the childhood-onset obesity associated with mutations in POMC and MC4R genes (17). The role of hypothalamic NPY and AGRP in human body weight and neuroendocrine regulation is unknown (18). ...
Animal studies have demonstrated the importance of orexigenic NPY and agouti-related protein (AGRP) hypothalamic neurons, which are inhibited by the adipocyte hormone leptin, in the regulation of body weight and neuroendocrine secretion. We have examined NPY and AGRP neurons in postmortem human hypothalami from controls, Prader-Willi syndrome and other obese subjects, using quantitative immunocytochemistry (ICC) and in situ hybridization, to identify causes of leptin resistance in human obesity. Using combined ICC and in situ hybridization, AGRP, but not POMC, was colocalized with NPY in infundibular nucleus neurons. Infundibular nucleus (including median eminence) NPY ICC staining or mRNA expression, and AGRP ICC staining, increased with premorbid illness duration. NPY ICC staining and mRNA expression were reduced in obese subjects, but AGRP ICC staining was unchanged, correcting for illness duration. This suggests normal responses of NPY and AGRP neurons to peripheral signals, such as leptin and insulin, in human illness and obesity. The pathophysiology of obesity and illness-associated anorexia appear to lie in downstream or separate neuronal circuits, but the infundibular neurons may mediate neuroendocrine responses to illness. The implications for pharmacological treatment of human obesity are discussed.
... Roche et al. used single-strand conformational polymorphism analysis and DNA sequencing to screen the coding regions of NPY in 50 obese individuals compared with two non-obese control subjects and found no sequence variation among these individuals (19). They did not observe either of the two exonic variants (1201A3 G and 5325T3 C) in their French white sample, which appear to be quite common in Mexican Americans. ...
Recently, we reported evidence for linkage between neuropeptide Y (NPY) and both obesity and several obesity-related quantitative measures in a sample of Mexican Americans from Starr County, Texas. The purpose of this study was to investigate putative variation within the coding and promoter regions of NPY.
Five young, obese individuals (body mass index [BMI] 33 to 45 kg/m2, age 14 to 30 years); five adult, lean individuals (BMI 20 to 26 kg/m2, age 39 to 65 years); and five sibling pairs sharing no alleles that were identical by descent at a marker locus proximal to NPY were selected for fluorescence-based sequencing of approximately 1100 base pairs (bp) immediately 5' from the start site and all four exons of NPY. We identified a total of eight variant sites, including a 2-bp insertion/deletion (I/D) within a putative negative regulatory region (-880I/D) and a 17-bp deletion at the exon 1/intron 1 junction (69I/D). The -880I/D and 69I/D variants were typed in a separate random sample of Mexican Americans (N = 914) from Starr County, Texas.
Analyses of variance resulted in a significant association between -880I/D and waist-to-hip ratio (p = 0.041) in the entire sample and between -880I/D and BMI (p = 0.031), abdominal circumference (p = 0.044), and waist-to-hip ratio (p = 0.041) in a non-obese subsample (BMI < 30 kg/m2, n = 594). The 69I/D variant was observed in only one pedigree and does not appear to segregate with obesity within this pedigree.
This study reports newly identified common human sequence variation within the regulatory and coding sequence of NPY. Several variants were observed, and of those tested, the -880I/D promoter region variant may influence body fat patterning in non-obese individuals but does not appear to play a major role in the etiology of common forms of obesity in this population.
... Likewise, the NPY chromosomal locus showed no linkage to obesity in a French population. 22 No linkage with obesity was detected for the NPY or NPY5R loci in Pima Indians. 24 Linkage was recently observed between a quantitative trait locus in the vicinity of the murine NPY gene and body weight (logarithm of the odds, LOD score 3.1). ...
To investigate whether the neuropeptide Y receptor 5 gene (NPY5R) is associated with obesity in humans.
The NPY5R gene was screened for polymorphisms by direct sequencing in two groups of Pima Indians, selected for extremes of body mass index (BMI). Genotype frequencies were analyzed for association with BMI extreme.
Full-heritage Pima Indians, non-diabetic and not first degree relatives. Obese group: 19 M/24 F, BMI = 49+/-7 kg/m2 (mean+/-s.d.) age = 24+/-2 y, lean group: 16 M/16 F, BMI = 23+/-2 kg/m2, age = 27+/-3 y.
Initially, the entire gene (proximal promoter, exon 1A, coding sequence, 5' and 3' UTRs) was sequenced in a subset of 20 individuals. No variants were found in the coding sequence, however three novel single nucleotide polymorphisms were detected in the non-coding regions: (1) a C-->T transition located within the promoter 28 bp upstream of the exon 1A transcription start site; (2) a T-->C transition 94 bp downstream of the stop codon; and (3) a G-->A transition 432 bp downstream of the stop codon. The polymorphisms were then screened in all 75 subjects.
The polymorphisms had mean heterozygosities of 0.34-0.50 and were in strong linkage disequilibrium (P<0.001). Genotype frequencies differed significantly in lean and obese Pimas for P2 (P=0.04) and for a triple haplotype (P=0.02, Bonferroni corrected).
Considering the importance of this gene in regulation of body weight, the association of these polymorphisms with extremes of BMI in Pima Indians indicates that NPY5R, or a locus nearby, may contribute to susceptibility to obesity in this population.
