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.

Podwyższone stężenia lipokaliny-2 w surowicy krwi są związane ze wskaźnikami metabolizmu glukozy i metabolizmu kostnego w przebiegu cukrzycy typu 2

“…This study showed that serum LCN2 levels were positively associated with FIns, as well as HOMA-β, the index assessing basal β-cell function, suggesting that LCN2 may contribute to insulin secretion in T2DM. These data are in agreement with the findings in transgenic mice [10]. In these transgenic mice lacking LCN2 in osteoblasts, insulin secretion was shown to be reduced in response to glucose or arginine challenge while islet number and size, β-cell mass, and β-cell proliferation decreased in the pancreas.…”

“…LCN2 was also shown to reduce osteoblast differentiation and be involved in osteoblast-osteoclast coupling [8,9]. The latest study demonstrates that bone is the main source of LCN2 in mice [10]. In agreement to the findings in the animal models mentioned above, this study is the first report showing that serum LCN2 levels correlate to both BMD and BTMs in patients with T2DM.…”

“…As shown in Table III TG, TC, ALP, P1NP, CTX, femoral neck BMD, and lumbar BMD (Table IV). Because a recent study in an animal model revealed that bone-derived LCN2 is implicated in glucose metabolism, the relationship between LCN2 and bone was examined [10]. The multiple stepwise regression analysis showed that femoral neck BMD (β = -0.176, p = 0.033), P1NP (β = 0.181, p = 0.026), and CTX (β = -0.168, p = 0.037) were independent predictors of LCN2 in T2DM (Table V).…”

“…Most recently, Mosialou et al found that osteoblasts in mice expressed LCN2 at higher levels than white adipose tissue and other tissues. LCN2 derived from bone improved glucose tolerance and insulin sensitivity [10]. Their findings revealed the endocrine function of bone, which modulates glucose metabolism via LCN2.…”

Current Status of Sarcopenia in Korea: A Focus on Korean Geripausal Women

“…Thus, inhibition of MC receptor activity by infusion of an MC receptor antagonist or with the inverse agonist agouti-related protein results in increased food intake. 76,77) Megestrol acetate improves appetite and is associated with slight weight gain in patients with cancer, AIDS, and other underlying pathology. 78) 3.…”