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.

The BEACH Is Hot: A LYST of Emerging Roles for BEACH‐Domain Containing Proteins in Human Disease

“…Heterozygous mice for a gene trap disruption of Nbea were, surprisingly, not smaller than normal as described for the heterozygous mice generated by Su et al , and they showed no behavioral phenotype, as was suggested by the human autism studies. Instead, the heterozygous Nbea gene trap mice develop mild obesity due to increase in adipose tissue associated with increased eating . The obesity and over‐eating was responsive to leptin and naltrexone, suggesting that this form of obesity involved neurological signals .…”

Genetic and Genomic Response to Selection for Food Consumption in Drosophila melanogaster

“…The mammalian orthologues of rg are Neurobeachin ( Nbea ) and LPS-responsive, beige-like anchor ( Lrba ) (Volders et al 2012). Mice heterozygous for an Nbea null allele increased food intake and white adipose, while in humans, variants in Nbea are significantly associated with an increased body mass index (Olszewski et al 2012). NBEA interacts with the glycine receptor β subunit in the central nervous system, where it may help traffic neurotransmitters (del Pino et al 2011).…”

Neurobeachin regulates neurotransmitter receptor trafficking to synapses

“…Human mutations in LRBA cause a syndrome of immunological abnormalities (Lopez-Herrera et al, 2012). Heterozygous rearrangements in the human NBEA gene were detected in patients with autism (Castermans et al, 2003) or with multiple myeloma (O'Neal et al, 2009), and reduced Nbea expression causes overweight patients (Olszewski et al, 2012).…”