• A Corrigendum to this article was published on 14 June 2017
  • An Erratum to this article was published on 29 November 2017

Abstract

Bone has recently emerged as a pleiotropic endocrine organ that secretes at least two hormones, FGF23 and osteocalcin, which regulate kidney function and glucose homeostasis, respectively. These findings have raised the question of whether other bone-derived hormones exist and what their potential functions are. Here we identify, through molecular and genetic analyses in mice, lipocalin 2 (LCN2) as an osteoblast-enriched, secreted protein. Loss- and gain-of-function experiments in mice demonstrate that osteoblast-derived LCN2 maintains glucose homeostasis by inducing insulin secretion and improves glucose tolerance and insulin sensitivity. In addition, osteoblast-derived LCN2 inhibits food intake. LCN2 crosses the blood–brain barrier, binds to the melanocortin 4 receptor (MC4R) in the paraventricular and ventromedial neurons of the hypothalamus and activates an MC4R-dependent anorexigenic (appetite-suppressing) pathway. These results identify LCN2 as a bone-derived hormone with metabolic regulatory effects, which suppresses appetite in a MC4R-dependent manner, and show that the control of appetite is an endocrine function of bone.

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Acknowledgements

The authors are grateful to A. Tarasenco for technical assistance, the Histology and Metabolic Unit facility of the Diabetes and Endocrinology Research Center (DERC, NIDDK DK063608-07), R. Tomaino of the Taplin Mass Spectrometry Facility, Harvard Medical School and the Albert Einstein DRTC Animal Physiology Core (NIDDK DK20541). This work was supported by the National Institutes of Health R01AR054447, P01AG032959 and R01AR055931 to S.K., R01DK100699 to K.W.W., R01DK52431 to R.L.L. and W.C., P30DK26687 to R.L.L. and W.C., P30DK063608 to R.L.L. and W.C., NOVO Nordisk to S.K and by the T32 Training Grant DK07328 to S.S.

Author information

Author notes

    • Jian-Min Liu
    •  & Antonio Maurizi

    Present addresses: Department of Endocrine and Metabolic Diseases, Shanghai Rui-jin Hospital, Shanghai Jiao-tong University School of Medicine, Shanghai 200025, China (J.-M.L.); Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila 67100, Italy (A.M.).

Affiliations

  1. Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA

    • Ioanna Mosialou
    • , Steven Shikhel
    • , Jian-Min Liu
    • , Antonio Maurizi
    • , Na Luo
    •  & Stavroula Kousteni
  2. Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510515, China

    • Zhenyan He
    •  & Yiru Huang
  3. Division of Hypothalamic Research, the University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9077, USA

    • Zhenyan He
    • , Yiru Huang
    •  & Kevin W. Williams
  4. Department of Medicine and Molecular Pharmacology, The Albert Einstein College of Medicine, Bronx, New York, New York 10461, USA

    • Haihong Zong
    •  & Jeffrey E. Pessin
  5. Biomedical Informatics Shared Resource, Department of Biomedical Informatics, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA

    • Richard A. Friedman
  6. Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA

    • Jonathan Barasch
  7. Naomi Berrie Diabetes Center and Division of Molecular Genetics, Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA

    • Patricia Lanzano
    • , Liyong Deng
    • , Rudolph L. Leibel
    •  & Wendy Chung
  8. Metabolic Bone Disease Unit, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA

    • Mishaela Rubin
  9. Department of Medicine Nephrology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA

    • Thomas Nickolas
  10. Naomi Berrie Diabetes Center and Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA

    • Lori M. Zeltser

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Contributions

I.M. and S.K. initiated the study, designed experiments and analysed data. I.M. and S.S. performed experiments and analysed data. N.L., J.-M.L. and A.M. helped with ICV infusions and bone phenotyping. H.Z. performed hyperglycemic clamps. R.A.F. analysed microarray data. J.B. provided Lcn2-reporter mice. P.L., L.D., R.L.L. and W.C. provided plasma samples of patients with MC4R mutations. M.R. and T.N. provided serum samples from men with type 2 diabetes. Z.H., Y.H. and K.W.W. performed the electrophysiology experiments. L.M.Z. and J.E.P. discussed data and manuscript. I.M. and S.K. wrote the manuscript. S.K. directed the research.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Stavroula Kousteni.

Reviewer Information Nature thanks M. Myers, R. Palmiter, M. Zaidi and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

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    Supplementary Figures

    The file contains gel source data, uncropped images of western, northern, southern blots and agarose gels.

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    Supplementary Table 1

    This file contains the microarray analysis of calvaria-derived osteoblasts from Foxo1osb-/- mice. Table contains genes with p<0.10, FDR<0.33 (where only 726 genes encoding for secreted proteins are taken into account in computing the FDR) and absolute value of the log2Fold change (FC)≥2, sorted by absolute value log2 FC.

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DOI

https://doi.org/10.1038/nature21697

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