MC4R-dependent Suppression of Appetite by Bone-Derived Lipocalin 2

Nature. 2017 Mar 16;543(7645):385-390. doi: 10.1038/nature21697. Epub 2017 Mar 8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Appetite Regulation / physiology*
  • Blood-Brain Barrier / metabolism
  • Bone and Bones / cytology
  • Bone and Bones / metabolism*
  • Cyclic AMP / metabolism
  • Eating / physiology
  • Female
  • Glucose / metabolism
  • Homeostasis
  • Hypothalamus / cytology
  • Hypothalamus / metabolism
  • Insulin / metabolism
  • Insulin Resistance
  • Insulin Secretion
  • Lipocalin-2 / metabolism*
  • Male
  • Mice
  • Neurons / metabolism
  • Obesity / metabolism
  • Osteoblasts / metabolism
  • Paraventricular Hypothalamic Nucleus / cytology
  • Receptor, Melanocortin, Type 4 / metabolism*
  • Thinness / metabolism


  • Insulin
  • Lipocalin-2
  • MC4R protein, mouse
  • Receptor, Melanocortin, Type 4
  • Lcn2 protein, mouse
  • Cyclic AMP
  • Glucose