title: The sympathetic tone mediates leptin's inhibition of insulin secretion by modulating osteocalcin bioactivity.
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.
authors.affiliation: Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Hinoi
authors.forename: Nan
authors.initials: N
authors.lastname: Gao
authors.forename: Dae Young
authors.initials: DY
authors.lastname: Jung
authors.forename: Vijay
authors.initials: V
authors.lastname: Yadav
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yoshizawa
authors.forename: Martin G
authors.initials: MG
authors.lastname: Myers
authors.forename: Streamson C
authors.initials: SC
authors.lastname: Chua
authors.forename: Jason K
authors.initials: JK
authors.lastname: Kim
authors.forename: Klaus H
authors.initials: KH
authors.lastname: Kaestner
authors.forename: Gerard
authors.initials: G
authors.lastname: Karsenty
mesh_terms: 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*
chemical_list: D007328:Insulin; D020738:Leptin; D015675:Osteocalcin