title: MC4R-dependent suppression of appetite by bone-derived lipocalin 2.
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.
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Mosialou
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Shikhel
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Liu
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Maurizi
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Luo
authors.affiliation: Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510515, China.|Division of Hypothalamic Research, the University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9077, USA.
authors.forename: Zhenyan
authors.initials: Z
authors.lastname: He
authors.affiliation: Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510515, China.|Division of Hypothalamic Research, the University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9077, USA.
authors.forename: Yiru
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Medicine and Molecular Pharmacology, The Albert Einstein College of Medicine, Bronx, New York, New York 10461, USA.
authors.forename: Haihong
authors.initials: H
authors.lastname: Zong
authors.affiliation: 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.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Friedman
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Barasch
authors.affiliation: 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.
authors.forename: Patricia
authors.initials: P
authors.lastname: Lanzano
authors.affiliation: 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.
authors.forename: Liyong
authors.initials: L
authors.lastname: Deng
authors.affiliation: 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.
authors.forename: Rudolph L
authors.initials: RL
authors.lastname: Leibel
authors.affiliation: Metabolic Bone Disease Unit, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Mishaela
authors.initials: M
authors.lastname: Rubin
authors.affiliation: Department of Medicine Nephrology, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Nickolas
authors.affiliation: 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.
authors.forename: Wendy
authors.initials: W
authors.lastname: Chung
authors.affiliation: Naomi Berrie Diabetes Center and Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.
authors.forename: Lori M
authors.initials: LM
authors.lastname: Zeltser
authors.affiliation: Division of Hypothalamic Research, the University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390-9077, USA.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Williams
authors.affiliation: Department of Medicine and Molecular Pharmacology, The Albert Einstein College of Medicine, Bronx, New York, New York 10461, USA.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Pessin
authors.affiliation: Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
authors.forename: Stavroula
authors.initials: S
authors.lastname: Kousteni
mesh_terms: D000818:Animals; D001069:Appetite Regulation / Q000502:physiology*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D004435:Eating / Q000502:physiology; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D000071068:Lipocalin-2 / Q000378:metabolism*; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism; D009765:Obesity / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology; D044105:Receptor, Melanocortin, Type 4 / Q000378:metabolism*; D013851:Thinness / Q000378:metabolism
chemical_list: C000717428:Fgf23 protein, mouse; D007328:Insulin; D000071068:Lipocalin-2; C574273:MC4R protein, mouse; D044105:Receptor, Melanocortin, Type 4; C071332:Lcn2 protein, mouse; D000089703:Fibroblast Growth Factor-23; D000242:Cyclic AMP; D005947:Glucose