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

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Thomas Rathjen, Xin Yan, Natalia L Kononenko, Min-Chi Ku, Kun Song, Leiron Ferrarese, Valentina Tarallo, Dmytro Puchkov, Gaga Kochlamazashvili, Sebastian Brachs, Luis Varela, Klara Szigeti-Buck, Chun-Xia Yi, Sonja C Schriever, Sudhir Gopal Tattikota, Anne Sophie Carlo, Mirko Moroni, Jan Siemens, Arnd Heuser, Louise van der Weyden & 9 more Andreas L Birkenfeld, Thoralf Niendorf, James F A Poulet, Tamas L Horvath, Matthias H Tschöp, Matthias Heinig, Mirko Trajkovski, Volker Haucke, Matthew N Poy

Original languageEnglish
Pages (from-to)1096-1103
Number of pages8
JournalNature Neuroscience
Volume20
Issue number8
Early online date19 Jun 2017
DOIs
Accepted/In press24 May 2017
E-pub ahead of print19 Jun 2017
Published1 Aug 2017

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Abstract

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.

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