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Neuronal Cell Adhesion Molecule 1 Regulates Leptin Sensitivity and Bone Mass

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Abstract

The central nervous system is widely known to exert control over our systemic physiology via several mechanisms including the regulation of skeletal metabolism. Neuronal circuits within the hypothalamus have been shown to impact bone mass via leptin-dependent and independent mechanisms; however, the full extent to which the brain controls bone homeostasis is not known. We previously identified cell adhesion molecule1 (Cadm1) as a regulator of body weight and energy homeostasis via its expression in multiple regions of the brain. Here, we show that loss of Cadm1 expression in excitatory neurons results in increased leptin sensitivity in addition to a concomitant reduction in bone mass. Femoral length, bone mineral content, diaphyseal cross-sectional area, and bone strength were all lower in Cadm1-deficient animals. Conversely, inducing expression of Cadm1 in excitatory neurons decreased leptin sensitivity and increased femoral length, bone mineral content, and diaphyseal cross-sectional area. Together, these results illustrate an essential role for this synaptic protein in the neuronal regulation of skeletal bone metabolism.

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Acknowledgements

The authors are grateful for the excellent technical assistance of Jytte Utoft (Aarhus University). This work was funded by the Helmholtz Gemeinschaft, the Helmholtz Metabolic Dysfunction Consortium, and the European Foundation for the Study of Diabetes (EFSD, Germany), and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD, Exc 229 to N.L.K.). The µCT scanner was kindly donated by the VELUX Foundation (Søborg, Denmark).

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Authors and Affiliations

  1. Max Delbrück Center for Molecular Medicine, Robert Rössle Strasse 10, 13125, Berlin, Germany

    Xin Yan & Matthew N. Poy

  2. CECAD Research Center, University of Cologne, Joseph-Stelzmann-Str. 26, 50931, Cologne, Germany

    Natalia L. Kononenko

  3. Institute of Biomedicine, Aarhus University, Wilhelm Meyers Allé 3, 8000, Aarhus C, Denmark

    Annemarie Brüel & Jesper Skovhus Thomsen

  4. Max Delbrück Center for Molecular Medicine, Robert Rössle Strasse 10, WFH C27, Rm 131, 13125, Berlin, Germany

    Matthew N. Poy

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  1. Xin Yan
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  2. Natalia L. Kononenko
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  3. Annemarie Brüel
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  4. Jesper Skovhus Thomsen
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  5. Matthew N. Poy
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Contributions

MNP conceived this study. XY, NLK, AB, JST, and MNP designed and performed the experiments. MNP and JST wrote the manuscript.

Corresponding author

Correspondence to Matthew N. Poy.

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The authors declare no competing interests.

Human and Animal Rights and Informed Consent

All animal research protocols were approved by the Landesamt für Gesundheit und Soziales Berlin (LAGeSo). This article does not contain any studies with human participants performed by any of the authors.

Electronic Supplementary Material

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223_2017_361_MOESM1_ESM.pdf

Supplementary Fig. 1: Loss of CADM1 in the brain of Slc17a6-Cre, Cadm1 flox/flox mice. (A) Double immunostaining of Cadm1 (green) and VGLUT2 (red) identifies co-localization of Cadm1 and VGLUT2 (yellow) in the dentate gyrus of the hippocampus. (B) Double immunostaining of Cadm1 (green) and VGLUT2 (red) identifies co-localization of Cadm1 and VGLUT2 (yellow) in the medial habenula. Dotted white boxes indicate the areas magnified to the left. Supplementary material 1 (PDF 2986 kb)

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Yan, X., Kononenko, N.L., Brüel, A. et al. Neuronal Cell Adhesion Molecule 1 Regulates Leptin Sensitivity and Bone Mass. Calcif Tissue Int 102, 329–336 (2018). https://doi.org/10.1007/s00223-017-0361-5

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  • DOI: https://doi.org/10.1007/s00223-017-0361-5

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