Neuropeptide Y polymorphism significantly magnifies diabetes and cardiovascular disease risk in obesity: the Hoorn Study

Jaakkola, Ulriikka; Kallio, Johanna; Heine, Robert J.; Nijpels, Giel; Hart, Leen M. ‘t; Maassen, J. A.; Bouter, Lex M.; Stehouwer, Coen D.A.; Dekker, Joost

doi:10.1038/sj.ejcn.1602964

Cited by 15 publications

(9 citation statements)

References 10 publications

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“…Interestingly, these tendencies occurred without major differences in WAT depot weights or at the level of hepatosteatosis in the OE-NPY DBH male mice. This suggests that increased NPY may have a diabetogenic effect in the context of obesity and supports the association of the L7P polymorphism with an earlier onset of diabetes in the obese human population [14]. …”

Section: Discussionsupporting

confidence: 72%

“…The NPY 1228T > C polymorphism (rs16139), which causes an amino acid substitution of Leucine 7 to Proline 7 (L7P) in the signal peptide [9] is functional, enhancing the secretion of NPY [10, 11]. It is associated with an earlier onset of type 2 diabetes in carriers of L7P [12], as well as with other traits of the metabolic syndrome [13] especially in obese subjects [14]. Recently, it was reported that there is a gender difference in the NPY-mediated effects of the Proline 7 allele [15].…”

Section: Introductionmentioning

confidence: 99%

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Diet-Induced Obesity in Mice Overexpressing Neuropeptide Y in Noradrenergic Neurons

Ruohonen

Vähätalo

Savontaus

2012

International Journal of Peptides

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Neuropeptide Y (NPY) is a neurotransmitter associated with feeding and obesity. We have constructed an NPY transgenic mouse model (OE-NPYDBH mouse), where targeted overexpression leads to increased levels of NPY in noradrenergic and adrenergic neurons. We previously showed that these mice become obese on a normal chow. Now we aimed to study the effect of a Western-type diet in OE-NPYDBH and wildtype (WT) mice, and to compare the genotype differences in the development of obesity, insulin resistance, and diabetes. Weight gain, glucose, and insulin tolerance tests, fasted plasma insulin, and cholesterol levels were assayed. We found that female OE-NPYDBH mice gained significantly more weight without hyperphagia or decreased activity, and showed larger white and brown fat depots with no difference in UCP-1 levels. They also displayed impaired glucose tolerance and decreased insulin sensitivity. OE-NPYDBH and WT males gained weight robustly, but no difference in the degree of adiposity was observed. However, 40% of OE-NPYDBH but none of the WT males developed hyperglycaemia while on the diet. The present study shows that female OE-NPYDBH mice were not protected from the obesogenic effect of the diet suggesting that increased NPY release may predispose females to a greater risk of weight gain under high caloric conditions.

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Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Diet-Induced Obesity in Mice Overexpressing Neuropeptide Y in Noradrenergic Neurons

Ruohonen

Vähätalo

Savontaus

2012

International Journal of Peptides

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“…Furthermore, the L7P polymorphism is associated with IGT and an earlier onset of type 2 diabetes in carriers of p.L7P,[7879] especially in obese subjects. [80] Again the OE-NPY DBH mice display with similar phenotype: IGT associated with obesity. Recently, it was reported that there is a gender difference in the NPY-mediated effects of the P7 allele.…”

Section: Clinical Relevancementioning

confidence: 99%

Neuropeptide Y in the noradrenergic neurons induces the development of cardiometabolic diseases in a transgenic mouse model

Ruohonen

Pesonen²,

Savontaus

2012

Indian J Endocr Metab

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Neuropeptide Y (NPY) is a neuropeptide widely expressed in the brain and a peptide transmitter of sympathetic nervous system (SNS) co-released with noradrenaline (NA) in prolonged stress. Association of a gain-of-function polymorphism in the human NPY gene with dyslipideamia, diabetes and vascular diseases suggests that increased NPY plays a role in the pathogenesis of the metabolic syndrome in humans. In the hypothalamus, NPY plays an established role in the regulation of body energy homeostasis. However, the effects of NPY elsewhere in the brain and in the SNS are less explored. In order to understand the role of NPY co-expressed with NA in the sympathetic nerves and brain noradrenergic neurons, a novel mouse model overexpressing NPY in noradrenergic neurons was generated. The mouse displays metabolic defects such as increased adiposity, hepatosteatosis, and impaired glucose tolerance as well as stress-related hypertension and increased susceptibility to vascular wall hypertrophy. The mouse phenotype closely reflects the findings of the several association studies with human NPY gene polymorphisms, and fits with the previous work on the effects of stress-induced NPY release on metabolism and vasculature. Thus, in addition of promoting feeding and obesity in the hypothalamus, NPY expressed in the noradrenergic neurons in the brain and in the SNS induces the development of cardiometabolic diseases.

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“…As of 1 January 2009, a total of 27 candidate genes for obesity from the hypothalamic pathways have been examined (see overview in Table S1), including 21 genes reported to be associated with obesity‐related phenotypes in the last HOGM update (24). Since November 2005, new studies on 11 of these 21 genes have been published, showing that variants in the following genes are associated with the risk of obesity: AGRP (25,26), BDNF (27–29), GAD2 (30), HTR2A (31,32), LEPR (33–40), MC4R (42–53,56), NPY (54–56), NPY2R (57–60), POMC (61,62) and UBL5 (63) (Table S1). However, in addition to these positive studies, a few other studies were unable to reproduce the associations between genetic markers in AGRP (54), BDNF (26), GAD2 (64,65), LEPR (41,66–68), MC3R (49), MC4R (69–71), NPY (57,72) and NPY2R (73) with obesity‐related phenotypes.…”

Section: Association Studies In Genes In the Hypothalamic Pathwaysmentioning

confidence: 99%

Genetic variation in the hypothalamic pathways and its role on obesity

et al. 2009

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Over recent decades, the prevalence of obesity has increased dramatically worldwide. Although this epidemic is mainly attributable to modern (western) lifestyle, multiple twin and adoption studies indicate the significant role of genes in the individual's predisposition to becoming obese. As the hypothalamus plays a central role in controlling body weight, its regulatory circuits may represent a crucial system in the pathogenesis of the disorder. Genetic variations in genes in the hypothalamic pathways may therefore contribute to the susceptibility for obesity in humans and animals. We summarize current knowledge on the physiological role of the hypothalamus in body-weight regulation and review genetic studies on the hypothalamic candidate genes in relation to obesity. Together, data from functional and genetic studies as well as the new, common, obesity loci identified in genome-wide association scans support an important role for the hypothalamic genes in predisposing to obesity. However, findings are still inconclusive for many candidate genes. To improve our understanding of the genetic architecture of common obesity, we suggest that specific obesity phenotypes should be considered and different analytical approaches used. Such studies should consider multiple genes from the same physiological pathways, together with environmental risk factors.

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Neuropeptide Y polymorphism significantly magnifies diabetes and cardiovascular disease risk in obesity: the Hoorn Study

Cited by 15 publications

References 10 publications

Diet-Induced Obesity in Mice Overexpressing Neuropeptide Y in Noradrenergic Neurons

Diet-Induced Obesity in Mice Overexpressing Neuropeptide Y in Noradrenergic Neurons

Neuropeptide Y in the noradrenergic neurons induces the development of cardiometabolic diseases in a transgenic mouse model

Genetic variation in the hypothalamic pathways and its role on obesity

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