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Neurobeachin, a Regulator of Synaptic Protein Targeting, Is Associated with Body Fat Mass and Feeding Behavior in Mice and Body-Mass Index in Humans

By Pawel K. Olszewski, Jan Rozman, Josefin A. Jacobsson, Birgit Rathkolb, Siv Strömberg, Wolfgang Hans, Anica Klockars, Johan Alsiö, Ulf Risérus, Lore Becker, Sabine M. Hölter, Ralf Elvert, Nicole Ehrhardt, Valérie Gailus-Durner, Helmut Fuchs, Robert Fredriksson, Eckhard Wolf, Thomas Klopstock, Wolfgang Wurst, Allen S. Levine, Claude Marcus, Martin Hrabě de Angelis, Martin Klingenspor, Helgi B. Schiöth and Manfred W. Kilimann

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

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:3305408
Provided by: PubMed Central

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