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

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.