¹Department of Trauma and Reconstructive Surgery, BG Trauma Center Tübingen, Siegfried Weller Institute for Trauma Research, Eberhard Karls University Tübingen, Tübingen, Deutschland
²Department of Systems Toxicology, Leibniz Institute for Work Physiology and Human Factors (IfADo) at TU Dortmund, Dortmund, Deutschland
³Department of Trauma and Reconstructive Surgery, BG Trauma Center Tübingen, Eberhard Karls University Tübingen, Tübingen, Deutschland

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Objectives and questions: Obesity has emerged as a global health crisis, with growing evidence linking it to metabolic disturbances, and impaired bone homeostasis. However, the mechanisms underlying vitamin D deficiency in obesity and its impact on bone quality remain unclear. This study aims to explore the interaction between obesity-related vitamin D deficiency and bone metabolism alterations using a high-fat diet-induced obesity mouse model to identify potential therapeutic targets for improving bone health in obese individuals.

Material and methods: 24 male C57Bl6/N mice were fed either a standard diet (SD) or a Western diet (WD; 40 kcal% carbohydrate, 40 kcal% fat, 20 kcal% protein) ad libitum for 48 weeks. Body weight was recorded weekly, while blood glucose levels were measured and liver and bones were collected at week 48. Liver RNA-seq was used to analyze vitamin D metabolism associated genes, while bone microarchitecture and biomechanical properties were assessed using micro-CT and three-point bending test. Histology and RT-PCR were performed to examine markers for vascular structures, Vitamin D receptor, and inflammation in the bone. Mann-Whitney-U Test tested statistical significance; significance was assumed to be p<0.05.

Results: The WD group showed a significantly higher weight, and blood glucose levels exhibited an upward trend. Liver RNA-seq revealed a significant reduction in CYP2R1, CYP27A1, and DHCR7, key enzymes in vitamin D metabolism, in the WD group. Micro-CT analysis showed significantly lower bone density in WD group (p = 0.0003). Biomechanical testing suggested a trend towards increased bone stiffness in the WD group (p = 0.0610).

RT-PCR analysis demonstrated decreased vitamin D receptor and elevated osteoclast markers in WD bones. However, no differences were observed in osteoblast markers. Expression of angiogenic factors CD31 and VEGF showed a decreased trend in WD bones, while inflammatory markers showed no significant differences. Histological analysis revealed that perilipin was significantly increased in the WD bones and vascular staining indicated a lower number of vascular structures in WD bones.

Discussion and conclusions: Our findings reveal that obesity induced by WD significantly reduces the activity of enzymes involved in vitamin D metabolism in the liver. Furthermore, Vitamin D deficiency primarily leads to bone loss by promoting osteoclast activity and bone resorption. These findings strongly suggest that restoring normal vitamin D metabolism or vitamin D supplementation could be a promising treatment of bone loss in obese patients, providing critical evidence for the clinical management of osteoporosis in obesity.