title: 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.affiliation: Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney, Australia. tara@anzac.edu.au
authors.forename: Tara C
authors.initials: TC
authors.lastname: Brennan-Speranza
authors.forename: Holger
authors.initials: H
authors.lastname: Henneicke
authors.forename: Sylvia J
authors.initials: SJ
authors.lastname: Gasparini
authors.forename: Katharina I
authors.initials: KI
authors.lastname: Blankenstein
authors.forename: Uta
authors.initials: U
authors.lastname: Heinevetter
authors.forename: Victoria C
authors.initials: VC
authors.lastname: Cogger
authors.forename: Dmitri
authors.initials: D
authors.lastname: Svistounov
authors.forename: Yaqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Cooney
authors.forename: Frank
authors.initials: F
authors.lastname: Buttgereit
authors.forename: Colin R
authors.initials: CR
authors.lastname: Dunstan
authors.forename: Caren
authors.initials: C
authors.lastname: Gundberg
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Seibel
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects* / Q000494:pharmacology; D003345:Corticosterone / Q000009:adverse effects* / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects* / Q000235:genetics; D005938:Glucocorticoids / Q000009:adverse effects* / Q000494:pharmacology; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007333:Insulin Resistance / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D015675:Osteocalcin / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics
chemical_list: D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D015675:Osteocalcin; D003345:Corticosterone