title: Human neuropeptide Y signal peptide gain-of-function polymorphism is associated with increased body mass index: possible mode of function.
abstract: Neuropeptide Y (NPY) has been implicated in the control of food intake and energy balance based on many observations in animals. We have studied single nucleotide polymorphisms (SNPs) within the regulatory and coding sequences of the human NPY gene. One variant (1128 T>C), which causes an amino acid change from leucine to proline at codon 7 in the signal peptide of NPY, was associated with increased body mass index (BMI) in two separate Swedish populations of normal and overweight individuals. In vitro transcription and translation studies indicated the unlikelihood that this signal peptide variation affects the site of cleavage and targeting or uptake of NPY into the endoplasmic reticulum (ER). However, the mutant, and to a lesser extent the wild-type, signal peptide by themselves markedly potentiated NPY-induced food intake, as well as hypothalamic NPY receptor signaling. Our findings in humans strongly indicate that the NPY signaling system is implicated in body weight regulation and suggest a new and unexpected functional role of a signal peptide.
authors.affiliation: Center for Genomics and Bioinformatics, Karolinska Institutet, Stockholm SE-171 77, Sweden. Bo.Ding@meb.ki.se
authors.forename: Bo
authors.initials: B
authors.lastname: Ding
authors.forename: Björn
authors.initials: B
authors.lastname: Kull
authors.forename: Zhurong
authors.initials: Z
authors.lastname: Liu
authors.forename: Salim
authors.initials: S
authors.lastname: Mottagui-Tabar
authors.forename: Håkan
authors.initials: H
authors.lastname: Thonberg
authors.forename: Harvest F
authors.initials: HF
authors.lastname: Gu
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Brookes
authors.forename: Lars
authors.initials: L
authors.lastname: Grundemar
authors.forename: Christina
authors.initials: C
authors.lastname: Karlsson
authors.forename: Anders
authors.initials: A
authors.lastname: Hamsten
authors.forename: Peter
authors.initials: P
authors.lastname: Arner
authors.forename: Claes-Göran
authors.initials: CG
authors.lastname: Ostenson
authors.forename: Suad
authors.initials: S
authors.lastname: Efendic
authors.forename: Magnus
authors.initials: M
authors.lastname: Monné
authors.forename: Gunnar
authors.initials: G
authors.lastname: von Heijne
authors.forename: Per
authors.initials: P
authors.lastname: Eriksson
authors.forename: Claes
authors.initials: C
authors.lastname: Wahlestedt
mesh_terms: D000818:Animals; D015992:Body Mass Index; D004252:DNA Mutational Analysis; D004305:Dose-Response Relationship, Drug; D004435:Eating; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009478:Neuropeptide Y / Q000008:administration & dosage / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011485:Protein Binding; D021382:Protein Sorting Signals / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013548:Sweden
chemical_list: D009478:Neuropeptide Y; D021382:Protein Sorting Signals; D011993:Recombinant Fusion Proteins