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Osteoblasts mediate the adverse effects of glucocorticoids on fuel metabolism

Year: 2012
Type: article
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.
DOI: 10.1172/jci63377
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
Institutions: The University of Sydney, Anzac Research Institute, German Rheumatism Research Centre, Charité – Universitätsmedizin Berlin, Berlin-Brandenburger Centrum für Regenerative Therapien, Concord Repatriation General Hospital, Garvan Institute of Medical Research, Yale University
Language: English
Open Access status: green
Funders: Yale University, Deutsche Forschungsgemeinschaft, University of New South Wales, Bundesministerium für Bildung und Forschung, National Institutes of Health, National Health and Medical Research Council, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: Osteoblast and Glucocorticoid-Induced Metabolic Dysfunction, G3611049175, The effects of cortisone on bone forming cells, G4261561784, Core Center. Yale Core Center for Musculoskeletal Disorders, G802442861, G9000313501
OpenAlex ID: W2107958082
FWCI: 6.423
Cites: 58
Cited by: 187
Related to: 10