Screening for mutations in the neuropeptide Y Y5 receptor gene in cohorts belonging to different weight extremes

Rosenkranz, K.; Hinney, Anke; Ziegler, Andreas; Prittwitz, S von; Barth, Nikolaus; Roth, Helmut; Mayer, Hermann; Siegfried, Wolfgang; Lehmkuhl, Gerd; Poustka, Fritz; Schmidt, M H; Schäfer, Helmut; Remschmidt, Helmut; Hebebrand, Johannes

doi:10.1038/sj.ijo.0800550

Cited by 47 publications

(15 citation statements)

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“…20 ± 22 Furthermore, a silent single nucleotide polymorphism (allele frequency 11%) within the NPY5R coding sequence showed no evidence of linkage or association with BMI in 160 obese children and adolescents, 128 underweight subjects and 58 anorexic patients. 23 This polymorphism was also detected in the present study in ®ve Caucasians (allele frequency 6%), but not in Pima Indians and was not analyzed further. Likewise, the NPY chromosomal locus showed no linkage to obesity in a French population.…”

Section: Discussionmentioning

confidence: 57%

Novel polymorphisms in the neuropeptide-Y Y5 receptor associated with obesity in Pima Indians

et al. 2000

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OBJECTIVE: To investigate whether the neuropeptide Y receptor 5 gene (NPY5R) is associated with obesity in humans. DESIGN: 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. SUBJECTS: Full-heritage Pima Indians, non-diabetic and not ®rst degree relatives. Obese group: 19 Ma24 F, BMI 49 AE 7 kgam 2 (mean AE s.d.) age 24 AE 2 y, lean group: 16 Ma16 F, BMI 23 AE 2 kgam 2 , age 27 AE 3 y. MEASUREMENTS: Initially, the entire gene (proximal promoter, exon 1A, coding sequence, 5 H and 3 H 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. RESULTS: The polymorphisms had mean heterozygosities of 0.34 ± 0.50 and were in strong linkage disequilibrium (P`0.001). Genotype frequencies differed signi®cantly in lean and obese Pimas for P2 (P 0.04) and for a triple haplotype (P 0.02, Bonferroni corrected). CONCLUSION: 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.

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Section: Discussionmentioning

confidence: 57%

Novel polymorphisms in the neuropeptide-Y Y5 receptor associated with obesity in Pima Indians

et al. 2000

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“…This allele was transmitted from the mother who had no history of any eating disorder. Association and transmission disequilibrium studies pertaining to variations and polymorphisms within the NPYY1R and NPYY5R and AN were negative (13).…”

Section: Appetite-regulating Peptidesmentioning

confidence: 99%

Anorexia nervosa in female adolescents: endocrine and bone mineral density disturbances

Argente

2002

European Journal of Endocrinology

145

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Anorexia nervosa (AN) is a chronic childhood psychiatric illness that involves a reduction in caloric intake, loss of weight and amenorrhea, either primary or secondary. The diagnostic criteria for AN have been established by the American Psychiatric Association. The prevalence of this disease amongst adolescents and young adults is between 0.5 and 1% and the incidence of new cases per year is approximately 5-10/100 000 between 15 and 19 years of age. A number of endocrine and metabolic disturbances have been described in patients with AN including amenorrhea-oligomenorrhea, delayed puberty, hypothyroidism, hypercortisolism, IGF-I deficiency, electrolyte abnormalities, hypoglycemia and hypophosphatemia, among others. In addition to prolonged amenorrhea, osteopenia and osteoporosis are the most frequent complications leading to clinically relevant fractures and increased fracture risk throughout life. Patients exhibit an alteration in the hypothalamic -pituitary -gonadal axis, which is responsible for the menstrual disorders. The increase in gonadotropin secretion that can be observed after ponderal recuperation suggests that malnutrition could be the most important mechanism involved in the decrease in gonadotropin secretion. The loss of fat tissue as a consequence of nutrient restriction has been associated with hypoleptinemia and abnormal secretion of peptides implicated in food control (neuropeptide Y, melanocortins and corticotropin-releasing factor, among others). A review of the endocrine abnormalities, disturbances in neurotransmitters, as well as a detailed analysis of bone markers and bone mineral density in patients with AN is described.

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“…There were genotype differences in lean and obese Pima Indians for P2 and for a 3 SNP haplotype [100]. A silent single nucleotide polymorphism within the NPY5-R coding sequence showed no evidence of association with BMI in children and adolescents [101]. 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.…”

Section: Link Between Npy Obesity and Insulin Resistancementioning

confidence: 97%

Appetite Regulatory Peptides and Insulin Resistance

Orbetzova¹

2012

Insulin Resistance

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In addition to leptin and insulin, receptors for ghrelin are also located on arcuate AgRP/NPY neurons, which are activated by central ghrelin administration. Furthermore, peripheral ghrelin administration activates neurons in the ARC and AgRP and NPY have been demonstrated to be requisite mediators of the hyperphagia induced by systemic ghrelin [11]. So, meal-generated satiety signals from the GI tract do interact with longer-term adiposity signals, such as insulin and leptin in energy balance [8].NPY is one of the most abundant peptides of the hypothalamus and one of the most potent orexigenic factors. The majority of neurons expressing NPY in the hypothalamus are found within the ARC and most co-express AgRP [14]. Synthesis and release of NPY are both regulated by leptin binding to its hypothalamic receptor. NPY links afferents reflecting the nutritional status of the organism from endocrine, gastrointestinal, and central and peripheral nervous systems to effectors of energy intake and expenditure [15]. NPY stimulates appetite inducing hyperphagia, increase of fat depots, decrease of thermogenesis, and suppression of sympathetic activity. NPY is known to be involved in other physiological functions, such as cardiovascular regulation, affective disorder, memory retention, neuroendocrine control. When leptin levels increase after food intake, the latter binds to its receptors in the hypothalamus which leads to discontinuation of NPY secretion [5,16]. The decrease of NPY concentration in obesity probably plays a role of a counterregulatory factor intended to prevent further weight gain. Thus, NPY becomes one of the main regulators of food intake, body weight and energy expenditure.Ghrelin is a fast-acting hormone, seemingly playing a role in meal initiation. Secreted predominantly from the stomach, ghrelin is the natural ligand for the growth hormone secretagogue-receptor (GHS-R) in the pituitary gland, thus fulfilling the criteria of a brain- gut peptide [5,6]. Although the majority of ghrelin is produced peripherally, there are ghrelin immunoreactive neurons within the hypothalamus that have terminals on hypothalamic NPY/AgRP, POMC and corticotropin releasing hormone (CRH) neurons [17], as well as orexin fibres in the LHA [18]. It was found that ghrelin acts to promote appetite in two ways-directly, by depolarizing the orexigenic NPY/AgRP neurons, and indirectly, by increasing the tonic inhibition exerted by the NPY/AgRP neurons over the anorexigenic POMC/CART neurons. Both of these ultimately enhance appetite [4,17,18]. The ability of ghrelin to increase food intake and body weight is mediated through the stimulation of NPY production in the hypothalamic ARC, where it antagonizes the inhibitory effect on NPY secretion displayed by leptin and insulin [19].The purpose of this chapter is to provide background information on the relationship between the main appetite regulatory peptides NPY and ghrelin, and insulin resistance. The role of NPY and ghrelin in food intake and body weight control in humans, and their ...

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Screening for mutations in the neuropeptide Y Y5 receptor gene in cohorts belonging to different weight extremes

Cited by 47 publications

References 30 publications

Novel polymorphisms in the neuropeptide-Y Y5 receptor associated with obesity in Pima Indians

Novel polymorphisms in the neuropeptide-Y Y5 receptor associated with obesity in Pima Indians

Anorexia nervosa in female adolescents: endocrine and bone mineral density disturbances

Appetite Regulatory Peptides and Insulin Resistance

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