Osteoblasts mediate the adverse effects of glucocorticoids on fuel metabolism
Tara C. Brennan-Speranza, … , Hong Zhou, Markus J. Seibel
Tara C. Brennan-Speranza, … , Hong Zhou, Markus J. Seibel
Published October 24, 2012
Citation Information: J Clin Invest. 2012;122(11):4172-4189. https://doi.org/10.1172/JCI63377.
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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 1

Targeted disruption of glucocorticoid signaling in osteoblasts profoundly affects glucocorticoid-induced changes in body composition and blood lipids.

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Targeted disruption of glucocorticoid signaling in osteoblasts profoundl...
(A) End point (day 28) body weight of WT and Tg mice treated with 1.5 mg corticosterone (1.5 mg GC) per week or placebo. (B) Body weight of treated WT and Tg mice over the 4-week period. (C) Fat mass in WT and Tg mice at day 28 measured by dual-energy x-ray absorptiometry. (D) Adipose cells per mm2 in H&E-stained sections of gonadal fat pads following 28 days of treatment. (E) Serum triglyceride levels of treated WT and Tg mice over the 4-week period. (F) Serum cholesterol levels of treated WT and Tg mice over the 4-week period. *P < 0.05, #P < 0.01, †P < 0.001 compared with respective genotype placebo-treated controls; ‡P < 0.05, **P < 0.01, ##P < 0.001 WT 1.5 mg GC compared with Tg 1.5 mg GC (2-way ANOVA followed by post-hoc analysis; repeated-measures ANOVA followed by post-hoc analysis for time-dependent measurements; error bars represent SEM).