Abstract
In the context of global aging, osteoporosis has emerged as a significant public health concern, with a relatively high prevalence observed in plateau regions. This study aimed to investigate the effects and underlying mechanisms of high-fat diet (HFD) and hypoxic conditions on bone metabolism in mice. The mice were subjected to different dietary regimens (a HFD versus a normal diet) and placed in a hypoxic environment. This study explored relevant mechanisms through comprehensive assessments, including body and bone morphological indices, pathological examinations, biochemical analyses, evaluation of gut microbiota diversity, and metabolomics approaches. The results indicated that, compared with those in the control group, the body weight, Lee's index, body mass index (BMI), and body fat percentage of the HFD-fed group were significantly greater. Additionally, the femoral microstructure was compromised, bone metabolic markers were disrupted, inflammatory responses were heightened, gut microbiota diversity was altered, and specific intestinal metabolites such as Anserine were downregulated, whereas L-carnosine was upregulated. Spearman correlation analysis and network visualization elucidated the multifactorial influence mechanism of a HFD on bone metabolism under hypoxic conditions. These factors interconnect to form a complex network that drives osteoporosis development. Notably, L-carnosine occupies a central position within this network, serving as a key hub for interactions among various factors. Under the dual stressors of hypoxia and a HFD, this network becomes imbalanced, leading to bone metabolic disorders and osteoporosis. This study provides insights into the multifactorial mechanisms of osteoporosis induced by a HFD and hypoxia in mice, offering a foundation for subsequent research and preventive strategies for osteoporosis in plateau areas.