NMN prevents obesity-induced osteoporosis by promoting mitophagy to restore type H vessels.

Obesity-induced osteoporosis is a growing global health challenge, necessitating more therapeutic strategies. Emerging evidence links the reduction of bone-specific type H vessels to osteoporosis due to their crucial role in angiogenesis-osteogenesis coupling. Nicotinamide Mononucleotide (NMN) is known to improve metabolic diseases, but its role in regulating type H vessels in obesity-induced osteoporosis remains unclear. An obesity-induced osteoporosis mouse model was established using a high-fat diet (HFD). In vitro, primary bone marrow mesenchymal stem cells (BMSCs) and human umbilical vein endothelial cells (HUVECs) were stimulated with palmitic acid (PA) to mimic a high-fat environment. Bones were evaluated using Micro-CT. The angiogenic capacity of HUVECs was examined by scratch assay. Potential targets of NMN in restoring type H vessels were explored via network pharmacology. Signaling pathways were investigated using immunofluorescence, western blot, and real-time PCR. NMN significantly inhibited HFD-induced osteoporosis by restoring impaired type H vessels in obese mice, thereby enhancing angiogenesis-osteogenesis coupling. In vitro, NMN rescued the PA-induced dysfunction in BMSCs and HUVECs, promoting osteogenic differentiation and migratory capacity, respectively. Mechanistically, NMN rescued HFD-impaired mitophagy in type H vessels via inhibiting Src activation, and inhibited obesity-induced polyamine accumulation. This effect was supported by restored mitochondrial membrane potential, enhanced LC3/TOMM20 co-localization, and upregulation of mitophagy-related genes. These findings demonstrate that NMN protects against obesity-induced osteoporosis by restoring type H vessels and enhancing angiogenesis-osteogenesis coupling, a process mediated by the Src/LC3 signaling pathway and subsequent mitophagy promotion. Our study elucidates a novel mechanism and highlights NMN as a promising therapeutic agent for treating obesity-related osteoporosis.