Regulatory mechanism of leptin in bone metabolism

Sun Long; Wu Haiyang; Tong Linjian; Liu Rui; Yang Weiguang; Xiao Jian; Liu Lice; Sun Zhiming

doi:10.12307/2026.736

Abstract：BACKGROUND:Recent studies have revealed that leptin participates in bone metabolism regulation through complex multidimensional mechanisms involving the central nervous system,peripheral direct actions,and the"gut-bone axis." OBJECTIVE:To systemically review the latest research advances in leptin-mediated bone metabolism regulation. METHODS:A systematic literature search was conducted in databases including PubMed and CNKI,covering publications up to April 2025.The search terms included"leptin,leptin receptor,bone metabolism,osteoblasts,osteoclasts,gut microbiota,osteoporosis"in English and Chinese,respectively.According to the inclusion criteria,a total of 80 articles were included for review. RESULTS AND CONCLUSION:Leptin directly promotes osteogenic differentiation of bone marrow mesenchymal stem cells while inhibiting adipogenesis,a process closely linked to vitamin D metabolism.The newly identified second ligand of the leptin receptor,angiopoietin-like protein 4,drives heterotopic ossification,explaining the unique phenotypes observed in leptin receptor mutation models.Histone deacetylase 6 enhances leptin sensitivity by modulating receptor acetylation.Gut microbiota regulates leptin levels via short-chain fatty acids,and fecal microbiota transplantation from young donors increases bone mass in aged osteoporotic models.Leptin exhibits distinct central and peripheral effects:it inhibits trabecular bone formation via the hypothalamus while directly promoting cortical bone mineralization.These discoveries provide novel insights for developing multi-system therapeutic strategies targeting the"gut-brain-bone"axis.Future research should focus on resolving key challenges such as leptin resistance mechanisms and central delivery efficiency to advance precision medicine for metabolic bone diseases.