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Osteoblasts mediate the adverse effects of glucocorticoids on fuel metabolism


Long-term glucocorticoid treatment is associated with numerous adverse outcomes, including weight gain, insulin resistance, and diabetes; however, the pathogenesis of these side effects remains obscure. Glucocorticoids also suppress osteoblast function, including osteocalcin synthesis. Osteocalcin is an osteoblast-specific peptide that is reported to be involved in normal murine fuel metabolism. We now demonstrate that osteoblasts play a pivotal role in the pathogenesis of glucocorticoid-induced dysmetabolism. Osteoblast-targeted disruption of glucocorticoid signaling significantly attenuated the suppression of osteocalcin synthesis and prevented the development of insulin resistance, glucose intolerance, and abnormal weight gain in corticosterone-treated mice. Nearly identical effects were observed in glucocorticoid-treated animals following heterotopic (hepatic) expression of both carboxylated and uncarboxylated osteocalcin through gene therapy, which additionally led to a reduction in hepatic lipid deposition and improved phosphorylation of the insulin receptor. These data suggest that the effects of exogenous high-dose glucocorticoids on insulin target tissues and systemic energy metabolism are mediated, at least in part, through the skeleton.

Type Journal
ISBN 1558-8238 (Electronic) 0021-9738 (Linking)
Authors Brennan-Speranza, T. C.; Henneicke, H.; Gasparini, S. J.; Blankenstein, K. I.; Heinevetter, U.; Cogger, V. C.; Svistounov, D.; Zhang, Y.; Cooney, G. J.; Buttgereit, F.; Dunstan, C. R.; Gundberg, C.; Zhou, H.; Seibel, M. J.;
Published Date 2012-01-01
Published Volume 122
Published Issue 11
Published Pages 4172-89
Status Published in-print
OpenAccess link to author's accepted manuscript version