Postnatal osteoblast-specific Sirt1 ablation directs bone remodeling and systemic glucolipid homeostasis.

Sirtuin 1 (Sirt1) plays a pivotal role in maintaining energy homeostasis; however, the crosstalk of Sirt1 in bone remodeling and energy expenditure has not been well understood. In this study, tamoxifen (TAM)-induced osteoblast-specific Sirt1 conditional knockout (cKO) mice were generated by crossing Col1a1-CreERT2 mice with Sirt1 floxed mice, and these mice exhibited a lower-bone-mass phenotype associated with declined bone formation and accelerated bone resorption. Despite no significant change in glucose tolerance, Sirt1 cKO mice displayed a modest insulin resistance as determined by impaired insulin tolerance tests and reduced hepatic insulin sensitivity and showed lipid disturbance characterized by adipocyte expansion/hypertrophy, enhanced lipid synthesis, and a potential defect in fatty acid oxidation (FAO) in inguinal white adipose tissue (iWAT). These metabolic disorders might be associated with decreased serum osteocalcin (OC) and its undercarboxylated form (ucOC) and the impaired FAO and WNT/β-catenin pathways in osteoblasts. Further analysis showed that silencing Sirt1 in osteoblasts contributed to downregulation of enzymatic mediators of FAO and reduced cellular levels of ATP and FFAs, which may be associated with the impaired WNT/β-catenin pathway in vivo and in vitro. Furthermore, treatment with the β-catenin agonist rescued the impairment of osteoblastic differentiation and FAO caused by Sirt1 knockout, which can be effectively blunted by etomoxir, a clinically approved FAO inhibitor. In conclusion, these data indicate that manipulation of osteoblast Sirt1 involves in fatty acid utilization and systemic glucolipid metabolism through β-catenin signaling.