Endocrine Abstracts (2018) 56 PL2 | DOI: 10.1530/endoabs.56.PL2

Bone Regulates the Brain to Control Appetite

Stavroula Kousteni


USA.


The discovery of the multiple endocrine functions of bone on the control of energy metabolism raised the question of whether several bone-derived hormones may exist that contribute to the regulation of metabolic functions such glucose tolerance, insulin sensitivity and energy expenditure, or whether they elicit a yet unanticipated endocrine function\. In response to this question a known hormone with a previously unidentified action was found to mediate a new metabolic function of bone: appetite. We have found Lipocalin 2 (LCN2), a previously thought adipokine, as an osteoblast-enriched secreted protein regulating food intake. Inactivation of Lcn2 specifically in osteoblasts (Lcn2osb-/- mice) increases blood glucose levels fat mass and body weight, decreases serum insulin and leads to glucose intolerance and insulin resistance. These effects result mainly from a 23.7% increase in food intake which is first detected at 3 weeks of age and remains elevated thereafter. In contrast, inactivation of Lcn2 in adipocytes has no effect on any of metabolic parameters. LCN2 is secreted by osteoblasts, crosses the blood brain barrier (BBB), binds to the melanocortin 4 receptor (MC4R) in the paraventricular and ventromedial neurons of the hypothalamus and activates the MC4R-dependent anorexigenic pathway. In addition, LCN2 has a physiological role in the regulation of feeding. LCN2 serum levels in fasted and refed wild type mice increased 3-fold after refeeding. This was to be due to a 1.6 fold increase in Lcn2 expression by osteoblast osteoblasts since Lcn2 expression by adipocytes was not altered. Intraperitoneal administration of recombinant LCN2 to fasted Lcn2-/- mice immediately after refeeding suppressed food intake within 1 hour and decreased body weight gain within 2 hours as efficiently as in WT mice. These observations identify Lcn2 as an osteoblast-derived anorexigenic hormone and regulation of appetite as a novel endocrine function of bone.

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