The sympathetic tone mediates leptin's inhibition of insulin secretion by modulating osteocalcin bioactivity.
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.
Hinoi
Eiichi
E
Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Gao
Nan
N
Jung
Dae Young
DY
Yadav
Vijay
V
Yoshizawa
Tatsuya
T
Myers
Martin G
MG
Chua
Streamson C
SC
Kim
Jason K
JK
Kaestner
Klaus H
KH
Karsenty
Gerard
G
D000818:Animals; D006801:Humans; D006946:Hyperinsulinism / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D020738:Leptin / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism; D015675:Osteocalcin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000378:metabolism*
D007328:Insulin; D020738:Leptin; D015675:Osteocalcin