Long-term Western diet feeding impairs hepatic vitamin D metabolism and promotes bone loss in mice.

Obesity and metabolic dysfunction-associated fatty liver disease (MAFLD) are increasingly recognized as risk factors for skeletal fragility, yet the mechanisms linking these conditions to impaired bone health remain poorly defined. The liver is central to vitamin D homeostasis through 25-hydroxylation, while skeletal responsiveness relies on vitamin D receptor (VDR) signaling. Disruption of either process may compromise bone remodeling. In this study, we investigated the long-term effects of Western diet (WD) feeding on hepatic vitamin D metabolism and bone integrity in a mouse model. Male C57BL/6N mice were fed a standard diet (SD) or WD for 48 weeks. WD-fed mice developed obesity, hepatic injury, and trabecular bone deterioration characterized by reduced bone mineral density and increased trabecular separation. Although trabecular architecture was compromised, three-point bending revealed no significant impairment in cortical bone mechanical properties. Histological analyses showed increased bone marrow adiposity and macrophage/monocyte lineage cells. Bone gene expression profiling indicated enhanced osteoclastogenic signaling. Hepatic transcriptomics demonstrated marked downregulation of key 25-hydroxylases (Cyp2r1, Cyp27a1) and vitamin D-binding protein, accompanied by reduced circulating 25‑hydroxyvitamin D. Bone tissue also exhibited decreased VDR protein abundance. Together, these findings suggest that long-term WD-induced obesity and hepatic dysfunction impair hepatic vitamin D metabolism and diminish skeletal vitamin D responsiveness, contributing to bone fragility. Targeting the liver-bone axis and restoring vitamin D homeostasis may provide therapeutic potential for obesity-related bone loss. See also the graphical abstract(Fig. 1).