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

Hinoi E, Gao N, Jung DY, Yadav V, Yoshizawa T, Myers MG, Chua SC, Kim JK, Kaestner KH, Karsenty G - J. Cell Biol. (2008)

Bottom Line: In this study, we show that leptin, which instead inhibits insulin secretion, partly uses the sympathetic nervous system to fulfill this function.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

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.

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Leptin regulates insulin secretion in part through the neuronal pathway. (A) ITT in 2-wk-old ob/ob mice. (B and C) Serum insulin and blood glucose in ob/ob mice. (D) Gene expression in pancreas or islets of 2-wk-old ob/ob mice. (E) Quantification of insulin/Ki67 immunoreactive cells in islets of 2-wk-old ob/ob mice. (F and G) Serum insulin and blood glucose in adipocyte-deficient (adp-def) mice. (H) Gene expression in pancreas or islets of 2-wk-old adipocyte-deficient mice. (I–K) Quantification of insulin/Ki67 immunoreactive cells in islets, β-cell area, and β-cell mass of 2-wk-old adipocyte-deficient mice. (L–N) Glucose-stimulated insulin secretion by leptin in islets from WT, ob/ob, and L/L mice. (O) Serum insulin levels in 1-mo-old Leprsyn−/− mice. Error bars indicate mean + SEM. *, P < 0.05; **, P < 0.01; P1, newborn; 1W, 1 wk old; 2W, 2 wk old. Control in O indicates Synapsin-Cre mice. In L–N, the concentration of glucose in the culture media is indicated in millimolars.
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fig1: Leptin regulates insulin secretion in part through the neuronal pathway. (A) ITT in 2-wk-old ob/ob mice. (B and C) Serum insulin and blood glucose in ob/ob mice. (D) Gene expression in pancreas or islets of 2-wk-old ob/ob mice. (E) Quantification of insulin/Ki67 immunoreactive cells in islets of 2-wk-old ob/ob mice. (F and G) Serum insulin and blood glucose in adipocyte-deficient (adp-def) mice. (H) Gene expression in pancreas or islets of 2-wk-old adipocyte-deficient mice. (I–K) Quantification of insulin/Ki67 immunoreactive cells in islets, β-cell area, and β-cell mass of 2-wk-old adipocyte-deficient mice. (L–N) Glucose-stimulated insulin secretion by leptin in islets from WT, ob/ob, and L/L mice. (O) Serum insulin levels in 1-mo-old Leprsyn−/− mice. Error bars indicate mean + SEM. *, P < 0.05; **, P < 0.01; P1, newborn; 1W, 1 wk old; 2W, 2 wk old. Control in O indicates Synapsin-Cre mice. In L–N, the concentration of glucose in the culture media is indicated in millimolars.

Mentions: The fact that leptin and osteocalcin exert opposite functions on insulin secretion prompted us to test whether they act independently of each other or not. To avoid the confounding issue of insulin resistance, we analyzed insulin secretion in leptin-deficient (ob/ob) mice at birth and 1 and 2 wk of age because at those ages body weight, abdominal and total fat mass, triglyceride level, and insulin sensitivity are not altered by the absence of leptin (Fig. 1 A and Fig. S1, A–D, available at http://www.jcb.org/cgi/content/full/jcb.200809113/DC1).


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

Hinoi E, Gao N, Jung DY, Yadav V, Yoshizawa T, Myers MG, Chua SC, Kim JK, Kaestner KH, Karsenty G - J. Cell Biol. (2008)

Leptin regulates insulin secretion in part through the neuronal pathway. (A) ITT in 2-wk-old ob/ob mice. (B and C) Serum insulin and blood glucose in ob/ob mice. (D) Gene expression in pancreas or islets of 2-wk-old ob/ob mice. (E) Quantification of insulin/Ki67 immunoreactive cells in islets of 2-wk-old ob/ob mice. (F and G) Serum insulin and blood glucose in adipocyte-deficient (adp-def) mice. (H) Gene expression in pancreas or islets of 2-wk-old adipocyte-deficient mice. (I–K) Quantification of insulin/Ki67 immunoreactive cells in islets, β-cell area, and β-cell mass of 2-wk-old adipocyte-deficient mice. (L–N) Glucose-stimulated insulin secretion by leptin in islets from WT, ob/ob, and L/L mice. (O) Serum insulin levels in 1-mo-old Leprsyn−/− mice. Error bars indicate mean + SEM. *, P < 0.05; **, P < 0.01; P1, newborn; 1W, 1 wk old; 2W, 2 wk old. Control in O indicates Synapsin-Cre mice. In L–N, the concentration of glucose in the culture media is indicated in millimolars.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2606962&req=5

fig1: Leptin regulates insulin secretion in part through the neuronal pathway. (A) ITT in 2-wk-old ob/ob mice. (B and C) Serum insulin and blood glucose in ob/ob mice. (D) Gene expression in pancreas or islets of 2-wk-old ob/ob mice. (E) Quantification of insulin/Ki67 immunoreactive cells in islets of 2-wk-old ob/ob mice. (F and G) Serum insulin and blood glucose in adipocyte-deficient (adp-def) mice. (H) Gene expression in pancreas or islets of 2-wk-old adipocyte-deficient mice. (I–K) Quantification of insulin/Ki67 immunoreactive cells in islets, β-cell area, and β-cell mass of 2-wk-old adipocyte-deficient mice. (L–N) Glucose-stimulated insulin secretion by leptin in islets from WT, ob/ob, and L/L mice. (O) Serum insulin levels in 1-mo-old Leprsyn−/− mice. Error bars indicate mean + SEM. *, P < 0.05; **, P < 0.01; P1, newborn; 1W, 1 wk old; 2W, 2 wk old. Control in O indicates Synapsin-Cre mice. In L–N, the concentration of glucose in the culture media is indicated in millimolars.
Mentions: The fact that leptin and osteocalcin exert opposite functions on insulin secretion prompted us to test whether they act independently of each other or not. To avoid the confounding issue of insulin resistance, we analyzed insulin secretion in leptin-deficient (ob/ob) mice at birth and 1 and 2 wk of age because at those ages body weight, abdominal and total fat mass, triglyceride level, and insulin sensitivity are not altered by the absence of leptin (Fig. 1 A and Fig. S1, A–D, available at http://www.jcb.org/cgi/content/full/jcb.200809113/DC1).

Bottom Line: In this study, we show that leptin, which instead inhibits insulin secretion, partly uses the sympathetic nervous system to fulfill this function.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

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.

Show MeSH
Related in: MedlinePlus