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

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. Osteoblast-derived LCN2 activates the melanocortin 4 receptor in neurons of the paraventricular nucleus of the hypothalamus to suppress appetite, regulates insulin secretion and increases insulin sensitivity and glucose tolerance. Bone is considered to be a multifunction endocrine organ that secretes hormones to regulate kidney function and glucose homeostasis. Here, Stavroula Kousteni and colleagues identify lipocalin 2 (LCN2), a protein secreted by osteoblasts, which also maintains glucose homeostasis by inducing insulin secretion and improving glucose tolerance and insulin sensitivity. Remarkably, LCN2 crosses the blood brain barrier, binds to the melanocortin 4 receptor (MC4R) in neurons of the hypothalamus and activates the MC4R-dependent anorexigenic pathway, which suppresses appetite. The authors conclude that LCN2 is a bone-derived metabolic regulatory hormone that can inhibit food intake and suggest that appetite is partially controlled by bone.