Role and mechanism of leptin in improving osteoporosis via the “gut–bone axis”

BACKGROUND: Osteoporosis is a systemic skeletal disorder characterized by reduced bone mass, microarchitectural deterioration, and increased fracture risk, particularly in postmenopausal women. Although current antiresorptive and anabolic therapies are effective in some patients, their use remains limited by safety concerns, restricted indications, and poor long-term adherence. Increasing evidence suggests that the gut-bone axis plays an important role in skeletal homeostasis, while leptin has emerged as a metabolic regulator with potential effects on bone remodeling. However, whether leptin alleviates osteoporosis through modulation of gut microbiota and microbiota-related metabolites remains unclear. Therefore, this study aimed to investigate the protective effects of leptin in ovariectomy-induced osteoporosis and to explore its potential associations with the gut microbiota-metabolite-bone regulatory mechanisms. METHODS: Female Sprague-Dawley rats were randomized into Sham, OVX, Sham+Leptin, and OVX+Leptin groups. BMD was measured by dual-energy X-ray absorptiometry, and trabecular microarchitecture was assessed by micro-CT and histology. Serum bone turnover markers were analyzed by ELISA. Gut microbiota composition was evaluated using 16 S rRNA sequencing. Serum metabolomics was performed using UHPLC-Orbitrap MS, and bile acids were quantified by LC-MS/MS. Bone protein expression was evaluated by immunohistochemistry. RESULTS: Leptin significantly increased BMD and improved trabecular microarchitecture in OVX rats, accompanied by normalization of ALP and OCN levels. Gut microbiota analysis showed that leptin treatment altered microbial composition, with increased relative abundances of taxa such as Akkermansia, Lachnospiraceae, and Muribaculaceae, and decreased abundance of Desulfovibrionaceae. Metabolomic profiling showed partial reversal of OVX-induced disturbances, particularly in unsaturated fatty acid and bile acids metabolism. Targeted bile acids analysis demonstrated restoration of hydrophilic bile acids following leptin treatment. Immunohistochemical analysis further showed that leptin treatment was associated with reduced RANKL expression and increased OPG expression. CONCLUSIONS: Leptin ameliorated OVX-induced osteoporosis in rats, accompanied by remodeling of the gut microbiota, partial restoration of serum metabolic and bile acids profiles, and changes in bone remodeling-related proteins. These findings suggest that the gut microbiota-metabolite-bone network may be involved in the skeletal effects of leptin, providing novel mechanistic insights and potential therapeutic strategies for osteoporosis management.