Regulation of body weight and energy homeostasis by neuronal Cell adhesion molecule 1

Susceptibility to obesity is linked to genes regulating neurotransmission, pancreatic β-cell function, and energy homeostasis. Genome-wide association studies identified an association between body mass index and two loci near Cell Adhesion Molecule1 (CADM1) and Cell Adhesion Molecule2 (CADM2), genes encoding membrane proteins mediating synaptic assembly. We show these respective risk variants associate with increased CADM1 and CADM2 expression in the hypothalamus of human subjects. Expression of both genes is elevated in obese mice and induction of Cadm1 in excitatory neurons facilitated weight gain while exacerbating energy expenditure. Loss of Cadm1 protected mice from obesity and tract-tracing analysis revealed Cadm1-positive innervation of POMC neurons via afferent projections originating from beyond the arcuate nucleus. Reducing Cadm1 expression in the hypothalamus and hippocampus promoted a negative energy balance and weight loss. These data identify roles for Cadm1-mediated neuronal input in weight regulation and provide insight into the central pathways contributing to human obesity.