MC4R-dependent suppression of appetite by bone-derived lipocalin 2

Ioanna Mosialou, Steven Shikhel, Jian-Min Liu, Antonio Maurizi, Na Luo, Zhenyan He, Yiru Huang, Haihong Zong, Richard A. Friedman, Jonathan Barasch, Patricia Lanzano, Liyong Deng, Rudolph L. Leibel, Mishaela Rubin, Thomas Nickolas, Wendy Chung, Lori M. Zeltser, Kevin W. Williams, Jeffrey E. Pessin and Stavroula Kousteni ()
Additional contact information
Ioanna Mosialou: College of Physicians and Surgeons, Columbia University
Steven Shikhel: College of Physicians and Surgeons, Columbia University
Jian-Min Liu: College of Physicians and Surgeons, Columbia University
Antonio Maurizi: College of Physicians and Surgeons, Columbia University
Na Luo: College of Physicians and Surgeons, Columbia University
Zhenyan He: Zhujiang Hospital, Southern Medical University
Yiru Huang: Zhujiang Hospital, Southern Medical University
Haihong Zong: The Albert Einstein College of Medicine, Bronx
Richard A. Friedman: Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University
Jonathan Barasch: College of Physicians and Surgeons, Columbia University
Patricia Lanzano: College of Physicians and Surgeons, Columbia University
Liyong Deng: College of Physicians and Surgeons, Columbia University
Rudolph L. Leibel: College of Physicians and Surgeons, Columbia University
Mishaela Rubin: Metabolic Bone Disease Unit, College of Physicians and Surgeons, Columbia University
Thomas Nickolas: College of Physicians and Surgeons, Columbia University
Wendy Chung: College of Physicians and Surgeons, Columbia University
Lori M. Zeltser: Columbia University
Kevin W. Williams: the University of Texas Southwestern Medical Center at Dallas
Jeffrey E. Pessin: The Albert Einstein College of Medicine, Bronx
Stavroula Kousteni: College of Physicians and Surgeons, Columbia University

Nature, 2017, vol. 543, issue 7645, 385-390

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature21697

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