Subjects

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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Acknowledgements

The authors would like to thank M. Gruhn and the Biozentrum Imaging Facility, University of Cologne, for access to Amira Software, and N. Zampieri, A. Plested, T. Breiderhoff, D. Matthäus, I. Park, C. Teng, T. Klüssendorf, H. Wessels, T. Willnow and M. Gotthardt for helpful discussions and assistance in the conduct of this work. This work was funded by the Helmholtz Gemeinschaft, the Helmholtz Metabolic Dysfunction Consortium, the Helmholtz Alliance ICEMED (Project 1210251 to T.N.), the European Research Council (ERC-2010-StG-260744 to M.N.P., ERC-2015-CoG-682422 to J.F.A.P., ERC-2011-StG-280565 to J.S., and ERC-2013-StG-336607 to M.T.), the US National Institutes of Health (R01-DK-111178, 1P01-AG-051459 and 1R56-AG-052986 to T.L.H.) the Swiss National Science Foundation Professorship (PP00P3_144886 to M.T.), the Deutsche Forschungsgemeinschaft (FOR-2143-Interneuron to J.F.A.P., Exc-257-NeuroCure to J.F.A.P. and V.H., and SFB958/A01 to V.H., and DFG BI1292/4-2 and DFG IRTG2251 to A.L.B.), the Federal Ministry of Education and Research (BMBF, Germany) (Project eMed:symAtrial (01ZX1408D to M.H.), the European Foundation for the Study of Diabetes (EFSD, Germany), the Thyssen Foundation, and the Kay Kendall Leukemia Foundation (KKLF Fellowship to L.v.d.W.). AAV reagents were provided by the UNC Vector Core facility and used with permission by K. Deisseroth (Stanford University).

Author information

Author notes

    • Thomas Rathjen
    •  & Xin Yan

    These authors contributed equally to this work.

Affiliations

  1. Max Delbrück Center for Molecular Medicine, Berlin, Germany.

    • Thomas Rathjen
    • , Xin Yan
    • , Min-Chi Ku
    • , Kun Song
    • , Leiron Ferrarese
    • , Sudhir Gopal Tattikota
    • , Anne Sophie Carlo
    • , Mirko Moroni
    • , Arnd Heuser
    • , Thoralf Niendorf
    • , James F A Poulet
    •  & Matthew N Poy
  2. Leibniz Institute for Molecular Pharmacology, Berlin, Germany.

    • Natalia L Kononenko
    • , Dmytro Puchkov
    • , Gaga Kochlamazashvili
    •  & Volker Haucke
  3. CECAD Research Center, University of Cologne, Cologne, Germany.

    • Natalia L Kononenko
  4. Cluster of Excellence NeuroCure, Neuroscience Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany.

    • Natalia L Kononenko
    • , Leiron Ferrarese
    • , James F A Poulet
    •  & Volker Haucke
  5. Berlin Ultrahigh Field Facility (B.U.F.F.), Max Delbrück Center for Molecular Medicine, Berlin, Germany.

    • Min-Chi Ku
    •  & Thoralf Niendorf
  6. University of Geneva, Medical Faculty, Department of Cell Physiology and Metabolism, Centre Médical Universitaire (CMU), Geneva, Switzerland.

    • Valentina Tarallo
    •  & Mirko Trajkovski
  7. Charité - Universitätsmedizin Berlin, Department of Endocrinology, Diabetes and Nutrition, Center for Cardiovascular Research, Berlin, Germany.

    • Sebastian Brachs
  8. Program in Integrative Cell Signaling and Neurobiology of Metabolism, Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.

    • Luis Varela
    • , Klara Szigeti-Buck
    •  & Tamas L Horvath
  9. Institute for Diabetes and Obesity, Helmholtz Centre for Health and Environment and Division of Metabolic Diseases, Technical University Munich, Munich, Germany.

    • Chun-Xia Yi
    • , Sonja C Schriever
    •  & Matthias H Tschöp
  10. Department of Pharmacology, University of Heidelberg, Heidelberg, Germany.

    • Jan Siemens
  11. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.

    • Louise van der Weyden
  12. Section of Metabolic Vascular Medicine and Paul Langerhans Institute Dresden of the Helmholtz Center Munich at University Hospital and Faculty of Medicine, TU Dresden, Medical Clinic III, University Clinic Dresden, Dresden, Germany.

    • Andreas L Birkenfeld
  13. Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK.

    • Andreas L Birkenfeld
  14. Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine, Berlin, Germany.

    • Thoralf Niendorf
  15. Department of Anatomy and Histology, University of Veterinary Sciences, Budapest, Hungary.

    • Tamas L Horvath
  16. Helmholtz Zentrum München, Institute of Computational Biology, Neuherberg, Germany.

    • Matthias Heinig

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Contributions

T.R. and M.N.P. conceived the study. T.R., X.Y., N.L.K., M.-C.K., K.S.-B., L.F., V.T., D.P., G.K., S.B., L.V., K.S., C.-X.Y., S.C.S., S.G.T., A.S.C., M.M., J.S., A.H., L.v.d.W., A.L.B., T.N., J.F.A.P., T.L.H., M.H.T., M.H., M.T., V.H. and M.N.P. designed and performed the experiments with help from all of the authors. V.H. and M.N.P. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Matthew N Poy.

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https://doi.org/10.1038/nn.4590

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