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.

  • Subscribe to Nature Neuroscience for full access:



Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.


  1. 1.

    et al. The lifetime medical cost burden of overweight and obesity: implications for obesity prevention. Obesity (Silver Spring) 16, 1843–1848 (2008).

  2. 2.

    & Genome-wide association studies in type 2 diabetes. Curr. Diab. Rep. 9, 164–171 (2009).

  3. 3.

    et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat. Genet. 38, 320–323 (2006).

  4. 4.

    Genome-wide association studies provide new insights into type 2 diabetes aetiology. Nat. Rev. Genet. 8, 657–662 (2007).

  5. 5.

    et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat. Genet. 41, 25–34 (2009).

  6. 6.

    et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat. Genet. 42, 937–948 (2010).

  7. 7.

    et al. Genetic studies of body mass index yield new insights for obesity biology. Nature 518, 197–206 (2015).

  8. 8.

    et al. SynCAM, a synaptic adhesion molecule that drives synapse assembly. Science 297, 1525–1531 (2002).

  9. 9.

    et al. SynCAMs organize synapses through heterophilic adhesion. J. Neurosci. 27, 12516–12530 (2007).

  10. 10.

    et al. N-glycosylation at the SynCAM (synaptic cell adhesion molecule) immunoglobulin interface modulates synaptic adhesion. J. Biol. Chem. 285, 34864–34874 (2010).

  11. 11.

    GTEx Consortium. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348, 648–660 (2015).

  12. 12.

    Bioinformatic characterization of the SynCAM family of immunoglobulin-like domain-containing adhesion molecules. Genomics 87, 139–150 (2006).

  13. 13.

    , , , & A very low carbohydrate ketogenic diet improves glucose tolerance in ob/ob mice independently of weight loss. Am. J. Physiol. Endocrinol. Metab. 297, E1197–E1204 (2009).

  14. 14.

    et al. Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23, 775–786 (1999).

  15. 15.

    et al. Role of brain insulin receptor in control of body weight and reproduction. Science 289, 2122–2125 (2000).

  16. 16.

    , , & Regulation of neuronal and glial proteins by leptin: implications for brain development. Endocrinology 140, 2755–2762 (1999).

  17. 17.

    et al. A guide to analysis of mouse energy metabolism. Nat. Methods 9, 57–63 (2011).

  18. 18.

    et al. Leptin-dependent control of glucose balance and locomotor activity by POMC neurons. Cell Metab. 9, 537–547 (2009).

  19. 19.

    et al. Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 71, 142–154 (2011).

  20. 20.

    et al. SynCAM 1 adhesion dynamically regulates synapse number and impacts plasticity and learning. Neuron 68, 894–906 (2010).

  21. 21.

    et al. Excitatory synaptic drive and feedforward inhibition in the hippocampal CA3 circuit are regulated by SynCAM 1. J. Neurosci. 36, 7464–7475 (2016).

  22. 22.

    & Silent synapses and the emergence of a postsynaptic mechanism for LTP. Nat. Rev. Neurosci. 9, 813–825 (2008).

  23. 23.

    Too many cooks? Intrinsic and synaptic homeostatic mechanisms in cortical circuit refinement. Annu. Rev. Neurosci. 34, 89–103 (2011).

  24. 24.

    et al. Topographic mapping of the synaptic cleft into adhesive nanodomains. Neuron 88, 1165–1172 (2015).

  25. 25.

    , & Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat. Neurosci. 2, 266–270 (1999).

  26. 26.

    , , & Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc. Natl. Acad. Sci. USA 96, 13427–13431 (1999).

  27. 27.

    et al. Role of the dorsal medial habenula in the regulation of voluntary activity, motor function, hedonic state, and primary reinforcement. J. Neurosci. 34, 11366–11384 (2014).

  28. 28.

    & The habenular nuclei: a conserved asymmetric relay station in the vertebrate brain. Philos Trans R Soc Lond B Biol Sci 364, 1005–1020 (2009).

  29. 29.

    et al. Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42, 983–991 (2004).

  30. 30.

    et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 123, 493–505 (2005).

  31. 31.

    et al. Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metab. 11, 286–297 (2010).

  32. 32.

    et al. Virus-assisted mapping of neural inputs to a feeding center in the hypothalamus. Science 291, 2608–2613 (2001).

  33. 33.

    & The genetics of type 2 diabetes: what have we learned from GWAS? Ann. NY Acad. Sci. 1212, 59–77 (2010).

  34. 34.

    & The bigger picture of FTO: the first GWAS-identified obesity gene. Nat. Rev. Endocrinol. 10, 51–61 (2014).

  35. 35.

    , & Place cells, grid cells and memory. Cold Spring Harb. Perspect. Biol. 7, a021808 (2015).

  36. 36.

    , , & Space in the brain: how the hippocampal formation supports spatial cognition. Phil. Trans. R. Soc. Lond. B 369, 20120510 (2013).

  37. 37.

    , & Synaptic plasticity in neuronal circuits regulating energy balance. Nat. Neurosci. 15, 1336–1342 (2012).

  38. 38.

    et al. Loss of TSLC1 causes male infertility due to a defect at the spermatid stage of spermatogenesis. Mol. Cell. Biol. 26, 3595–3609 (2006).

  39. 39.

    , & Metabolic pitfalls of CNS Cre-based technology. Cell Metab. 18, 21–28 (2013).

  40. 40.

    et al. Argonaute2 mediates compensatory expansion of the pancreatic β cell. Cell Metab. 19, 122–134 (2014).

  41. 41.

    & Immunocytochemistry and quantification of protein colocalization in cultured neurons. Nat. Protoc. 1, 1287–1296 (2006).

  42. 42.

    & A recurring problem with the analysis of energy expenditure in genetic models expressing lean and obese phenotypes. Diabetes 59, 323–329 (2010).

  43. 43.

    et al. Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice. Cell Metab. 14, 184–195 (2011).

  44. 44.

    et al. Gut microbiota orchestrates energy homeostasis during cold. Cell 163, 1360–1374 (2015).

  45. 45.

    et al. Synapse loss associated with abnormal PrP precedes neuronal degeneration in the scrapie-infected murine hippocampus. Neuropathol. Appl. Neurobiol. 26, 41–54 (2000).

  46. 46.

    et al. Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304, 110–115 (2004).

  47. 47.

    et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480–484 (2001).

  48. 48.

    GTEx Consortium. The Genotype-Tissue Expression (GTEx) project. Nat. Genet. 45, 580–585 (2013).

  49. 49.

    & Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. Ser. B Methodol. 57, 289–300 (1995).

Download references


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.


  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


  1. Search for Thomas Rathjen in:

  2. Search for Xin Yan in:

  3. Search for Natalia L Kononenko in:

  4. Search for Min-Chi Ku in:

  5. Search for Kun Song in:

  6. Search for Leiron Ferrarese in:

  7. Search for Valentina Tarallo in:

  8. Search for Dmytro Puchkov in:

  9. Search for Gaga Kochlamazashvili in:

  10. Search for Sebastian Brachs in:

  11. Search for Luis Varela in:

  12. Search for Klara Szigeti-Buck in:

  13. Search for Chun-Xia Yi in:

  14. Search for Sonja C Schriever in:

  15. Search for Sudhir Gopal Tattikota in:

  16. Search for Anne Sophie Carlo in:

  17. Search for Mirko Moroni in:

  18. Search for Jan Siemens in:

  19. Search for Arnd Heuser in:

  20. Search for Louise van der Weyden in:

  21. Search for Andreas L Birkenfeld in:

  22. Search for Thoralf Niendorf in:

  23. Search for James F A Poulet in:

  24. Search for Tamas L Horvath in:

  25. Search for Matthias H Tschöp in:

  26. Search for Matthias Heinig in:

  27. Search for Mirko Trajkovski in:

  28. Search for Volker Haucke in:

  29. Search for Matthew N Poy in:


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.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–15 and Supplementary Tables 1–3

  2. 2.

    Supplementary Methods Checklist