Osteoblasts mediate the adverse effects of glucocorticoids on fuel metabolism
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
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
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Research Article

Osteoblasts mediate the adverse effects of glucocorticoids on fuel metabolism

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

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Figure 7

Heterotopic expression of osteocalcin from day 8 reduces glucocorticoid-induced changes in body composition.

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Heterotopic expression of osteocalcin from day 8 reduces glucocorticoid-...
(A) Body weight as percentage of baseline of EV, wtOCN, and μOCN vector–receiving mice (vector administered via hTVI on day 8) treated with 1.5 mg corticosterone per week or placebo over the 4-week period. (B) Lean body mass of vector-receiving mice treated over the 4-week period. (C) Body fat mass of vector-receiving mice treated over the 4-week period. (D) Fat/lean mass ratio of vector-receiving mice treated over the 4-week period. (E) Serum triglyceride levels of vector-receiving mice treated over the 4-week period. (F) Serum cholesterol levels of vector-receiving mice treated over the 4-week period (“for all” indicates that significance applies to all groups at this time point). *P < 0.05, #P < 0.01, †P < 0.001 compared with respective vector-receiving placebo-treated controls; ‡P < 0.05, **P < 0.01 compared with other corticosterone-treated groups receiving wtOCN and μOCN vectors (repeated-measures ANOVA followed by post-hoc analysis; error bars represent SEM).