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 Nicholas, Wendy Chung, Lori M. Zeltser, Kevin W. Williams, Jeffrey E. Pessin, Stavroula Kousteni

Research output: Contribution to journalArticle

70 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)385-390
Number of pages6
JournalNature
Volume543
Issue number7645
DOIs
StatePublished - Mar 16 2017

Fingerprint

Receptor, Melanocortin, Type 4
Appetite
Bone and Bones
Osteoblasts
Hormones
Glucose
Homeostasis
Osteocalcin
Blood-Brain Barrier
Hypothalamus
Insulin Resistance
Molecular Biology
Eating
Lipocalin-2
Insulin
Kidney
Neurons
Proteins

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Mosialou, I., Shikhel, S., Liu, J. M., Maurizi, A., Luo, N., He, Z., ... Kousteni, S. (2017). MC4R-dependent suppression of appetite by bone-derived lipocalin 2. Nature, 543(7645), 385-390. https://doi.org/10.1038/nature21697

MC4R-dependent suppression of appetite by bone-derived lipocalin 2. / Mosialou, Ioanna; Shikhel, Steven; Liu, Jian Min; Maurizi, Antonio; Luo, Na; He, Zhenyan; Huang, Yiru; Zong, Haihong; Friedman, Richard A.; Barasch, Jonathan; Lanzano, Patricia; Deng, Liyong; Leibel, Rudolph L.; Rubin, Mishaela; Nicholas, Thomas; Chung, Wendy; Zeltser, Lori M.; Williams, Kevin W.; Pessin, Jeffrey E.; Kousteni, Stavroula.

In: Nature, Vol. 543, No. 7645, 16.03.2017, p. 385-390.

Research output: Contribution to journalArticle

Mosialou, I, Shikhel, S, Liu, JM, Maurizi, A, Luo, N, He, Z, Huang, Y, Zong, H, Friedman, RA, Barasch, J, Lanzano, P, Deng, L, Leibel, RL, Rubin, M, Nicholas, T, Chung, W, Zeltser, LM, Williams, KW, Pessin, JE & Kousteni, S 2017, 'MC4R-dependent suppression of appetite by bone-derived lipocalin 2', Nature, vol. 543, no. 7645, pp. 385-390. https://doi.org/10.1038/nature21697
Mosialou I, Shikhel S, Liu JM, Maurizi A, Luo N, He Z et al. MC4R-dependent suppression of appetite by bone-derived lipocalin 2. Nature. 2017 Mar 16;543(7645):385-390. https://doi.org/10.1038/nature21697
Mosialou, Ioanna ; Shikhel, Steven ; Liu, Jian Min ; Maurizi, Antonio ; Luo, Na ; He, Zhenyan ; Huang, Yiru ; Zong, Haihong ; Friedman, Richard A. ; Barasch, Jonathan ; Lanzano, Patricia ; Deng, Liyong ; Leibel, Rudolph L. ; Rubin, Mishaela ; Nicholas, Thomas ; Chung, Wendy ; Zeltser, Lori M. ; Williams, Kevin W. ; Pessin, Jeffrey E. ; Kousteni, Stavroula. / MC4R-dependent suppression of appetite by bone-derived lipocalin 2. In: Nature. 2017 ; Vol. 543, No. 7645. pp. 385-390.
@article{fbba7af58d5c4b3b84330b4bd7bc68bb,
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.",
author = "Ioanna Mosialou and Steven Shikhel and Liu, {Jian Min} and Antonio Maurizi and Na Luo and Zhenyan He and Yiru Huang and Haihong Zong and Friedman, {Richard A.} and Jonathan Barasch and Patricia Lanzano and Liyong Deng and Leibel, {Rudolph L.} and Mishaela Rubin and Thomas Nicholas and Wendy Chung and Zeltser, {Lori M.} and Williams, {Kevin W.} and Pessin, {Jeffrey E.} and Stavroula Kousteni",
year = "2017",
month = "3",
day = "16",
doi = "10.1038/nature21697",
language = "English (US)",
volume = "543",
pages = "385--390",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7645",

}

TY - JOUR

T1 - MC4R-dependent suppression of appetite by bone-derived lipocalin 2

AU - Mosialou, Ioanna

AU - Shikhel, Steven

AU - Liu, Jian Min

AU - Maurizi, Antonio

AU - Luo, Na

AU - He, Zhenyan

AU - Huang, Yiru

AU - Zong, Haihong

AU - Friedman, Richard A.

AU - Barasch, Jonathan

AU - Lanzano, Patricia

AU - Deng, Liyong

AU - Leibel, Rudolph L.

AU - Rubin, Mishaela

AU - Nicholas, Thomas

AU - Chung, Wendy

AU - Zeltser, Lori M.

AU - Williams, Kevin W.

AU - Pessin, Jeffrey E.

AU - Kousteni, Stavroula

PY - 2017/3/16

Y1 - 2017/3/16

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85015422700&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85015422700&partnerID=8YFLogxK

U2 - 10.1038/nature21697

DO - 10.1038/nature21697

M3 - Article

VL - 543

SP - 385

EP - 390

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7645

ER -