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J. Cell Biol. 183 (7): 1235-1242

Copyright © 2008 by the Rockefeller University Press.


The sympathetic tone mediates leptin's inhibition of insulin secretion by modulating osteocalcin bioactivity

Eiichi Hinoi1, Nan Gao2,3, Dae Young Jung4, Vijay Yadav1, Tatsuya Yoshizawa1, Martin G. Myers, Jr.5,6, Streamson C. Chua, Jr.7,8, Jason K. Kim4, Klaus H. Kaestner2,3, , and Gerard Karsenty1

1 Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032
2 Department of Genetics and 3 Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104
4 Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033
5 Department of Internal Medicine and 6 Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109
7 Department of Medicine and 8 Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 12461

Correspondence to Gerard Karsenty: gk2172{at}

Abstract: The osteoblast-secreted molecule osteocalcin favors insulin secretion, but how this function is regulated in vivo by extracellular signals is for now unknown. In this study, we show that leptin, which instead inhibits insulin secretion, partly uses the sympathetic nervous system to fulfill this function. Remarkably, for our purpose, an osteoblast-specific ablation of sympathetic signaling results in a leptin-dependent hyperinsulinemia. In osteoblasts, sympathetic tone stimulates expression of Esp, a gene inhibiting the activity of osteocalcin, which is an insulin secretagogue. Accordingly, Esp inactivation doubles hyperinsulinemia and delays glucose intolerance in ob/ob mice, whereas Osteocalcin inactivation halves their hyperinsulinemia. By showing that leptin inhibits insulin secretion by decreasing osteocalcin bioactivity, this study illustrates the importance of the relationship existing between fat and skeleton for the regulation of glucose homeostasis.

Abbreviations used in this paper: HA, hydroxyapatite; ICV, intracerebroventricular; ITT, insulin tolerance test; WT, wild type.

© 2008 Hinoi et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at

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