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

J. Cell Biol., 29 December 2008
Vol. 183, Issue 7, p. 1235-1242
DOI: 10.1083/jcb.200809113

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

  1. Eiichi Hinoi1,
  2. Nan Gao2,3,
  3. Dae Young Jung4,
  4. Vijay Yadav1,
  5. Tatsuya Yoshizawa1,
  6. Martin G. Myers Jr.5,6,
  7. Streamson C. Chua Jr.7,8,
  8. Jason K. Kim4,
  9. Klaus H. Kaestner2,3, and
  10. Gerard Karsenty1
  1. 1Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032
  2. 2Department of Genetics and 3Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104
  3. 4Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033
  4. 5Department of Internal Medicine and 6Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI 48109
  5. 7Department of Medicine and 8Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 12461
  1. Correspondence to Gerard Karsenty: gk2172{at}


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.

  • Submitted: 16 September 2008
  • Accepted: 24 November 2008


E. Hinoi, N. Gao, D. Y. Jung, V. Yadav, T. Yoshizawa, M. G. Myers, S. C. Chua, J. K. Kim, K. H. Kaestner, and G. Karsenty, The sympathetic tone mediates leptin's inhibition of insulin secretion by modulating osteocalcin bioactivity. J. Cell Biol. 183, 1235-1242 (2008).

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