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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 122 Issue 11 Pg. 4172-89 (Nov 2012) ISSN: 1558-8238 [Electronic] United States
• PMID: 23093779 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Glucocorticoids
• Osteocalcin
• Corticosterone

Topics

• Animals
• Anti-Inflammatory Agents (adverse effects, pharmacology)
• Corticosterone (adverse effects, pharmacology)
• Energy Metabolism (drug effects, genetics)
• Glucocorticoids (adverse effects, pharmacology)
• Glucose Intolerance (genetics, metabolism, pathology)
• Insulin Resistance (genetics)
• Mice
• Mice, Transgenic
• Osteoblasts (metabolism, pathology)
• Osteocalcin (biosynthesis, genetics)
• Rats
• Signal Transduction (drug effects, genetics)