MC4R-dependent suppression of appetite by bone-derived lipocalin 2.
Nature, 2017/03/16;543(7645):385-390.
Mosialou I[1], Shikhel S[1], Liu JM[1], Maurizi A[1], Luo N[1], He Z[2, 3], Huang Y[2, 3], Zong H[4], Friedman RA[5], Barasch J[6], Lanzano P[7], Deng L[7], Leibel RL[7], Rubin M[8], Nickolas T[9], Chung W[7], Zeltser LM[10], Williams KW[3], Pessin JE[4], Kousteni S[1]
Affiliations
PMID: 28273060DOI: 10.1038/nature21697
Impact factor: 69.504
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.
MeSH terms
Animals; Appetite Regulation; Blood-Brain Barrier; Bone and Bones; Cyclic AMP; Eating; Female; Fibroblast Growth Factor-23; Glucose; Homeostasis; Hypothalamus; Insulin; Insulin Resistance; Insulin Secretion; Lipocalin-2; Male; Mice; Neurons; Obesity; Osteoblasts; Paraventricular Hypothalamic Nucleus; Receptor, Melanocortin, Type 4; Thinness
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