Journal
JOURNAL OF CELL BIOLOGY
Volume 183, Issue 7, Pages 1235-1242Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1083/jcb.200809113
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Funding
- Japan Society for the Promotion of Science
- Uehara Memorial Foundation
- Kanae Foundation for the Promotion of Medical Science
- National Institutes of Health
- American Diabetes Association
- Escoublac, Inc
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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.
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