Endocrine Abstracts

Background: Bone marrow adipose tissue (BMAT) comprises >10% of total adipose mass in healthy humans and further increases in diverse clinical conditions, including obesity/diabetes, osteoporosis and following caloric restriction (CR). However, why BMAT increases during CR remains unknown. One possibility is that this is mediated by glucocorticoid (GC) excess. GC action on target tissues depends on circulating and intracellular concentrations of the active hormone (cortisol in humans; corticosterone in rats/mice). Most effects of endogenous glucocorticoid excess are mediated by 11b-hydroxysteroid dehydrogenase type 1 (11b-HSD1), which catalyses intracellular regeneration of active glucocorticoids from inert 11-keto forms. CR increases circulating GCs, and GC therapy increases BMAT; thus, we hypothesise that GC excess mediates BMAT expansion during CR.

Objectives: Determine 1) if bone marrow expresses 11b-HSD1; 2) if CR increases GC activity within bones; and 3) if ablation of 11b-HSD1 blocks CR-induced BMAT expansion.

Methods: 1) HSD11B1 mRNA was measured in bone marrow from hip-replacement patients. 2&3) Male and female C57BL/6J mice lacking 11b-HSD1 (Hsd11b1^Del1/Del1) or littermate controls (WT) were fed ad libitum (AL) or 70% of AL intake (CR) from 9 to 15 weeks of age and skeletal GC target gene expression determined. Body mass, composition, and plasma were measured weekly. At 15 weeks mice were euthanised. Plasma corticosterone and 11-dehydrocorticosterone were measured by ELISA or LC–MS/MS. Bone loss (calcified bones) and BMAT (decalcified, osmium-tetroxide-stained bones) were measured by micro-computed tomography.

Results: 1&2) 11b-HSD1 was expressed in bones and marrow of mice and humans. CR in mice increased expression of GC target genes in bone, suggesting increased GC action. 3) In WT and Hsd11b1^Del1/Del1 mice, CR decreased body and lean mass and increased circulating corticosterone. Consistent with previous studies, in both genotypes CR decreased fat mass only in male mice. Circulating 11-dehydrocorticosterone was significantly greater in AL and CR Hsd11b1^Del1/Del1 mice than WT controls. While CR-induced bone loss was negligible, CR-induced BMAT expansion occurred in females of both genotypes and in WT males, but not Hsd11b1^Del1/Del1 male mice.

Conclusions: CR increases GC action within bones; BMAT expansion is not sufficient for bone loss; and intracellular GC activation by 11b-HSD1 is required for CR-induced BMAT expansion in male, but not female mice. These findings highlight glucocorticoids as potential mediators of BMAT formation and identify novel sex-dependent differences in the skeletal and metabolic adaptations to caloric restriction.