Abstract
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.
Authors
Tara C. Brennan-Speranza, Holger Henneicke, Sylvia J. Gasparini, Katharina I. Blankenstein, Uta Heinevetter, Victoria C. Cogger, Dmitri Svistounov, Yaqing Zhang, Gregory J. Cooney, Frank Buttgereit, Colin R. Dunstan, Caren Gundberg, Hong Zhou, Markus J. Seibel
Figure 13
Schematic model of the effects exogenous high-dose glucocorticoids on insulin sensitivity and glucose handling in mice.
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ISSN: 0021-9738 (print), 1558-8238 (online)