11β-Hydroxysteroid dehydrogenase type 1 deficiency causes sexual dimorphism in body composition and bone mass in response to caloric restriction.

Caloric restriction (CR) alters energy metabolism and increases systemic glucocorticoid production, contributing to bone loss and bone marrow adipose tissue (BMAT) expansion. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) mediates the local amplification of glucocorticoids within these tissues, but its contribution to CR-induced skeletal alterations remains unclear. Eight-week-old male and female WT and global 11β-HSD1 KO mice were assigned to ad libitum feeding or 30% CR for 8 wk. Body composition was assessed by DXA, bone microarchitecture by micro-CT (μCT), biomechanics by 3-point bending, BMAT by histology, serum bone turnover markers, and corticosterone by ELISA. Caloric restriction reduced body weight and lean mass of both sexes and genotypes. Fat mass was decreased in males WT and KO but not in females, while bone mass was reduced significantly in WT and KO female CR. Micro-CT revealed trabecular and cortical deterioration in both WT and KO CR females. Bone marrow adipose tissue was increased in mice under CR in both sexes, regardless of genotype. KO mice exhibited elevated corticosterone during CR, suggesting compensatory hypothalamic-pituitary-adrenal activation. These results demonstrate that CR induces sex-dependent changes in mesenchymal tissues. Under CR, females preserved fat mass but lost bone mass, while males maintained bone mass despite fat loss. Both sexes experienced lean mass loss. The effects of 11β-HSD1 deletion were also sex-specific: female KO mice had higher trabecular and cortical parameters, and lean mass under ad libitum feeding, while male KO mice under CR showed increased lean mass and trabecular bone thickness. However, 11β-HSD1 deletion did not prevent BMAT expansion in either sex under CR.