TY - JOUR
T1 - Regulation of body weight and energy homeostasis by neuronal cell adhesion molecule 1
AU - Rathjen, Thomas
AU - Yan, Xin
AU - Kononenko, Natalia L
AU - Ku, Min-Chi
AU - Song, Kun
AU - Ferrarese, Leiron
AU - Tarallo, Valentina
AU - Puchkov, Dmytro
AU - Kochlamazashvili, Gaga
AU - Brachs, Sebastian
AU - Varela, Luis
AU - Szigeti-Buck, Klara
AU - Yi, Chun-Xia
AU - Schriever, Sonja C
AU - Tattikota, Sudhir Gopal
AU - Carlo, Anne Sophie
AU - Moroni, Mirko
AU - Siemens, Jan
AU - Heuser, Arnd
AU - van der Weyden, Louise
AU - Birkenfeld, Andreas L
AU - Niendorf, Thoralf
AU - Poulet, James F A
AU - Horvath, Tamas L
AU - Tschöp, Matthias H
AU - Heinig, Matthias
AU - Trajkovski, Mirko
AU - Haucke, Volker
AU - Poy, Matthew N
PY - 2017/8/1
Y1 - 2017/8/1
N2 - Susceptibility to obesity is linked to genes regulating neurotransmission, pancreatic beta-cell function and energy homeostasis. Genome-wide association studies have identified associations between body mass index and two loci near cell adhesion molecule 1 (CADM1) and cell adhesion molecule 2 (CADM2), which encode membrane proteins that mediate synaptic assembly. We found that these respective risk variants associate with increased CADM1 and CADM2 expression in the hypothalamus of human subjects. Expression of both genes was 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 essential roles for Cadm1-mediated neuronal input in weight regulation and provide insight into the central pathways contributing to human obesity.
AB - Susceptibility to obesity is linked to genes regulating neurotransmission, pancreatic beta-cell function and energy homeostasis. Genome-wide association studies have identified associations between body mass index and two loci near cell adhesion molecule 1 (CADM1) and cell adhesion molecule 2 (CADM2), which encode membrane proteins that mediate synaptic assembly. We found that these respective risk variants associate with increased CADM1 and CADM2 expression in the hypothalamus of human subjects. Expression of both genes was 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 essential roles for Cadm1-mediated neuronal input in weight regulation and provide insight into the central pathways contributing to human obesity.
KW - Animals
KW - Arcuate Nucleus of Hypothalamus/metabolism
KW - Body Weight/physiology
KW - Cell Adhesion Molecule-1
KW - Cell Adhesion Molecules/genetics
KW - Cell Adhesion Molecules, Neuronal/genetics
KW - Energy Metabolism/physiology
KW - Genome-Wide Association Study
KW - Homeostasis/genetics
KW - Immunoglobulins/genetics
KW - Membrane Proteins/metabolism
KW - Mice, Transgenic
KW - Neurons/metabolism
KW - Obesity/genetics
KW - Pro-Opiomelanocortin/metabolism
U2 - 10.1038/nn.4590
DO - 10.1038/nn.4590
M3 - Article
C2 - 28628102
SN - 1097-6256
VL - 20
SP - 1096
EP - 1103
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 8
ER -
