Life relies on the integration of external environmental stimuli and internal signals to balance fluctuations in nutrient availability to achieve homeostasis. 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. Furthermore, we show that serum LCN2 levels correlate with insulin levels and β-cell function, indices of healthy glucose metabolism, in genetic and diet-induced mouse models of obesity and in obese, healthy or pre-diabetic patients. However, LCN2 serum levels also correlate with body mass index (BMI) and insulin resistance in the same patients; and are increased in obese mice. To dissect this apparent discrepancy, we examined LCN2 effects in hyperphagia and β -cell function mouse models of obesity or β -cell destruction. Silencing Lcn2 expression increases hyperphagia, fat and body weight and worsens β -cell function and general metabolic dysfunction in obese, leptin receptor-deficient mice. Conversely, LCN2 increases β-cell numbers and promotes β-cell function after streptozotocin-induced β -cell failure by (STZ) and acts as a growth factor necessary for β -cell adaptation to higher metabolic load in mice. These results support a protective role for LCN2 in obesity-induced glucose intolerance and insulin resistance that stem from its ability to decrease food intake and promote adaptive β-cell proliferation.