The adipocyte-derived hormone leptin inhibits insulin production, in part by acting directly on pancreatic β cells; however, indirect effects of leptin are also involved. In contrast, osteocalcin, which is produced by osteoblasts, stimulates insulin secretion by β cells. Given that leptin also inhibits osteoblast activity, Hinoi et al. investigated whether it might affect osteocalcin activity. Serum insulin concentration was greater in leptin-deficient (ob/ob) mice than in wild-type (WT) mice, whereas serum glucose concentration was lower. Although leptin reduced insulin secretion by pancreatic islets isolated from ob/ob mice compared to that by untreated islets, this was not sufficient to account for the effect of leptin deficiency in vivo. Mice with leptin receptor–deficient neurons had higher serum insulin concentrations than did WT mice, whereas the concentration of the adrenergic receptor (AR) agonist epinephrine was lower, which is indicative of low sympathetic tone. The β-AR agonist isoproterenol decreased the amount of serum insulin in ob/ob mice compared with that in untreated mice. Serum insulin in mice whose osteoblasts were deficient in β2-AR (Adrβ2osb–/– mice) was higher than that in WT mice, and the β-AR antagonist propanolol increased serum insulin in WT mice compared with that in untreated mice. In addition, leptin decreased insulin production in WT, but not Adrβ2osb–/–, mice. Treatment of osteoblasts with isoproterenol increased their expression of the gene encoding Esp, a protein that inactivates osteocalcin. Indeed, knocking out Esp in ob/ob mice worsened their hyperinsulinemia. Thus, leptin, through its stimulation of sympathetic tone, decreased osteocalcin activity, thereby inhibiting insulin production by β cells. These data suggest an important role for crosstalk between fat and the skeleton in regulating glucose homeostasis.
E. Hinoi, N. Gao, D. Y. Jung, V. Yadav, T. Yoshizawa, M. G. Myers Jr., S. C. Chua Jr., J. K. Kim, K. H. Kaestner, G. Karsenty, The sympathetic tone mediates leptin’s inhibition of insulin secretion by modulating osteocalcin bioactivity. J. Cell Biol. 183, 1235–1242 (2008). [Abstract] [Full Text]