title: Neurobeachin, a regulator of synaptic protein targeting, is associated with body fat mass and feeding behavior in mice and body-mass index in humans.
abstract: Neurobeachin (Nbea) regulates neuronal membrane protein trafficking and is required for the development and functioning of central and neuromuscular synapses. In homozygous knockout (KO) mice, Nbea deficiency causes perinatal death. Here, we report that heterozygous KO mice haploinsufficient for Nbea have higher body weight due to increased adipose tissue mass. In several feeding paradigms, heterozygous KO mice consumed more food than wild-type (WT) controls, and this consumption was primarily driven by calories rather than palatability. Expression analysis of feeding-related genes in the hypothalamus and brainstem with real-time PCR showed differential expression of a subset of neuropeptide or neuropeptide receptor mRNAs between WT and Nbea+/- mice in the sated state and in response to food deprivation, but not to feeding reward. In humans, we identified two intronic NBEA single-nucleotide polymorphisms (SNPs) that are significantly associated with body-mass index (BMI) in adult and juvenile cohorts. Overall, data obtained in mice and humans suggest that variation of Nbea abundance or activity critically affects body weight, presumably by influencing the activity of feeding-related neural circuits. Our study emphasizes the importance of neural mechanisms in body weight control and points out NBEA as a potential risk gene in human obesity.
authors.affiliation: Functional Pharmacology Unit, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Pawel K
authors.initials: PK
authors.lastname: Olszewski
authors.forename: Jan
authors.initials: J
authors.lastname: Rozman
authors.forename: Josefin A
authors.initials: JA
authors.lastname: Jacobsson
authors.forename: Birgit
authors.initials: B
authors.lastname: Rathkolb
authors.forename: Siv
authors.initials: S
authors.lastname: Strömberg
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hans
authors.forename: Anica
authors.initials: A
authors.lastname: Klockars
authors.forename: Johan
authors.initials: J
authors.lastname: Alsiö
authors.forename: Ulf
authors.initials: U
authors.lastname: Risérus
authors.forename: Lore
authors.initials: L
authors.lastname: Becker
authors.forename: Sabine M
authors.initials: SM
authors.lastname: Hölter
authors.forename: Ralf
authors.initials: R
authors.lastname: Elvert
authors.forename: Nicole
authors.initials: N
authors.lastname: Ehrhardt
authors.forename: Valérie
authors.initials: V
authors.lastname: Gailus-Durner
authors.forename: Helmut
authors.initials: H
authors.lastname: Fuchs
authors.forename: Robert
authors.initials: R
authors.lastname: Fredriksson
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.forename: Thomas
authors.initials: T
authors.lastname: Klopstock
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.forename: Allen S
authors.initials: AS
authors.lastname: Levine
authors.forename: Claude
authors.initials: C
authors.lastname: Marcus
authors.forename: Martin Hrabě
authors.initials: MH
authors.lastname: de Angelis
authors.forename: Martin
authors.initials: M
authors.lastname: Klingenspor
authors.forename: Helgi B
authors.initials: HB
authors.lastname: Schiöth
authors.forename: Manfred W
authors.initials: MW
authors.lastname: Kilimann
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000293:Adolescent; D000818:Animals; D015992:Body Mass Index; D001933:Brain Stem / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002648:Child; D005247:Feeding Behavior; D005508:Food Deprivation; D005786:Gene Expression Regulation / Q000235:genetics; D056726:Genetic Association Studies; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
chemical_list: D002352:Carrier Proteins; D008565:Membrane Proteins; C498595:NBEA protein, human; C403265:Nbea protein, mouse; D009419:Nerve Tissue Proteins