Vitamin D is a fat-soluble vitamin that plays a vital role in maintaining bone health and regulating calcium-phosphorus metabolism. It also participates in numerous physiological functions such as immune modulation, anti-inflammatory activity, and antioxidant defense. In recent years, accumulating evidence has shown a close association between Vitamin D deficiency and obesity. Obesity is frequently associated with deficiencies in various micronutrients, with Vitamin D deficiency being the most prevalent (1), which may be attributed to its fat-soluble nature leading to sequestration in adipose tissue, chronic systemic inflammation, and reduced outdoor activity. Therefore, the high global prevalence of Vitamin D deficiency may be one of the key contributors to the rising obesity rates worldwide (2).

Vitamin D deficiency has been linked to multiple metabolic disorders, including dyslipidemia, insulin resistance, and type 2 diabetes (3, 4), all of which are common complications of obesity. Systematic reviews and meta-analyses have suggested that cholecalciferol supplementation may reduce body mass index (BMI) and waist circumference in overweight and obese individuals to a certain extent. However, data on more specific body composition metrics such as body fat percentage and waist-to-hip ratio remain limited (5).

In recent years, researchers have increasingly focused on the non-skeletal effects of Vitamin D, particularly its potential benefits on muscle function. Vitamin D deficiency is associated with muscle weakness, reduced exercise performance, and increased risk of falls, whereas supplementation may enhance muscle strength, improve repair processes, and boost endurance and overall physical function (6). Consequently, it has been proposed that Vitamin D supplementation may potentiate the effects of exercise interventions in improving weight and metabolic outcomes among overweight or obese adults, especially by synergistically optimizing body composition. At the mechanistic level, transcriptomic technology offers new insights into the potential synergy between Vitamin D and exercise. By analyzing gene expression changes under different conditions, transcriptomics can reveal how Vitamin D and exercise jointly regulate pathways in skeletal muscle, adipose tissue, and inflammation. Previous studies have suggested that Vitamin D may modulate signaling pathways such as AMPK, PPARγ, and NF-κB, thereby influencing lipid metabolism, energy homeostasis, and immune function (7–11). Thus, transcriptomics not only facilitates mechanistic understanding but may also serve as a novel molecular biomarker tool for evaluating intervention responses. Although existing studies provide preliminary evidence for the potential value of Vitamin D in obesity management, numerous unresolved issues remain, including optimal dosing, intervention duration, and the ideal combination model with exercise. Therefore, the current study systematically integrates transcriptomic data and clinical trial evidence to evaluate whether Vitamin D supplementation enhances the weight loss effects of exercise in overweight or obese adults.

Compared to previous studies, this review provides a more comprehensive evaluation of the role of Vitamin D supplementation in exercise-induced weight loss in overweight and obese populations. Given the heterogeneity in participant age, exercise modalities, and Vitamin D dosing across studies, we incorporated both transcriptomic and meta-analytic approaches to enhance scientific rigor. This review primarily focuses on the effects of Vitamin D supplementation on body composition and metabolic health in overweight/obese individuals, and further compares its effects on plasma 25-hydroxyvitamin D [25(OH)D] levels when combined with or without exercise. By integrating high-throughput molecular data with clinical evidence, we aim to provide a theoretical and practical framework for developing personalized obesity interventions based on a synergistic “nutrition–exercise–molecular target” strategy, especially for individuals seeking to improve their health through scientifically grounded methods.

Vitamin D is widely used in weight management among obese populations due to its role in chronic disease prevention and metabolic regulation (30). Exercise, as a safe and multifaceted intervention, can improve energy metabolism, mood states, and disease risk (31–33). In recent years, increasing research has attempted to incorporate Vitamin D supplementation into exercise programs to enhance their intervention effects. Transcriptomic analysis provides molecular-level evidence for this hypothesis. By integrating data from GSE271452 and GTEx skeletal muscle samples, 36 differentially expressed genes were identified, and enrichment analysis indicated that Vitamin D metabolic disturbances in obesity are primarily mediated through pathways related to lipid digestion and absorption, pancreatic secretion, calcium ion transport, and hormone metabolism. These disturbances may affect nutrient absorption in the gut and exacerbate Vitamin D deficiency. In selecting the experimental model, this study used cold-induced muscle shivering to simulate exercise intervention. Although this approach offers advantages in terms of ethics and control, its physiological mechanisms differ from those of real exercise interventions. Cold-induced energy metabolism regulation involves two mechanisms: shivering thermogenesis through muscle shivering and non-shivering thermogenesis mediated by brown adipose tissue (34, 35). In contrast, voluntary exercise is a more complex physiological adaptation process, involving active muscle contraction, cardiovascular system responses, and long-term metabolic reprogramming (36). The cold-induced muscle shivering model showed that, after intervention, genes related to Vitamin D response in the skeletal muscle of obese participants were significantly upregulated, activating metabolic pathways such as p53, TGF-β, and calcium signaling. This suggests that Vitamin D may be involved in energy metabolism regulation by modulating muscle remodeling and mitochondrial function. These findings are consistent with previous studies on Vitamin D’s role in regulating muscle synthesis, lipid metabolism, and insulin sensitivity (37–43), further supporting its potential mechanistic role in combined interventions. Although this model offers some insights, the indirect connection to actual exercise physiology needs further clarification in future studies, particularly concerning how Vitamin D might regulate muscle remodeling (44–46), mitochondrial function (47–49), and calcium signaling (50, 51) in the context of energy metabolism. Such explanations may help better understand the mechanisms underlying the role of Vitamin D in exercise interventions.

The results of the meta-analysis showed that, although Vitamin D combined with exercise did not demonstrate consistent improvements in weight, BMI, or body fat percentage, it did show certain advantages in reducing waist circumference (30). Subgroup analysis further revealed that the combined intervention was more effective in controlling weight and BMI in older adults (≥60 years) and in participants engaging in aerobic exercise, suggesting that individual characteristics and exercise modalities may modulate intervention effects. Additionally, previous studies have indicated that Vitamin D deficiency is strongly associated with obesity, metabolic syndrome, and cardiovascular disease, particularly in women and individuals with abdominal obesity (2, 52). Although calcitriol supplementation can modestly reduce BMI and waist circumference (53), its direct impact on weight remains limited. Combined interventions may work through multiple mechanisms, such as enhancing Vitamin D receptor (VDR) expression (54), modulating leptin levels (55), and improving gut microbiota and bile acid metabolism (40), thereby synergistically promoting fat metabolism. However, the results on whether exercise significantly elevates serum 25(OH)D levels remain inconsistent. Some studies suggest that endurance or mixed training may be effective, while resistance training alone has limited effects (56–59). Given that Vitamin D in obese populations is primarily stored in adipose tissue with limited bioavailability (60), combined interventions may be of greater clinical significance for this group (22, 26, 61). At the same time, Vitamin D levels are influenced by various factors such as diet, supplement intake, skin color, and sun exposure (62, 63). Therefore, future research should focus on variables such as VDR expression, baseline Vitamin D status, exercise intensity, and intervention duration, and use standardized, long-term follow-up RCT to further clarify the adaptability and mechanistic basis of “Vitamin D + exercise” interventions in different populations.

Moreover, in this study’s meta-analysis, we observed high I² values for some outcome measures, suggesting significant heterogeneity across studies. This heterogeneity may stem from differences in demographic characteristics such as age, gender distribution, baseline Vitamin D status, and methodological differences such as exercise modalities (e.g., aerobic, resistance, or multimodal training), intervention duration, frequency, and supplementation doses (ranging from 1,000 IU/d to 50,000 IU/w). Higher doses of Vitamin D may have a more significant impact on muscle function and fat metabolism, but this was not consistently reflected in the current analysis (29, 64, 65). To reduce bias due to heterogeneity, we used a random-effects model for the summary estimate and further explored the moderating effects of individual characteristics and intervention modalities through subgroup analysis. Notably, subgroup results showed that Vitamin D combined with exercise had a more significant impact on weight and BMI improvement in older adults (≥60 years) and those participating in aerobic exercise, suggesting that age has a clear physiological boundary, which is often used in previous studies to distinguish populations with significant differences in metabolic sensitivity. However, the studies included in the current analysis used multiple different serum 25(OH)D cutoffs (25 nmol/L, 50 nmol/L, and 75 nmol/L), and some studies cited multiple thresholds within the same paper (29), which limited the feasibility of this subgroup analysis. Although theoretically, both interventions may synergistically affect fat generation, reduce inflammation, and show potential in improving metabolic indicators, high-quality RCT are currently lacking to confirm their advantages in weight or body fat reduction (66–68). As such studies increase, especially with standardized reporting of Vitamin D status, this suggestion will have significant potential to refine target populations and intervention strategies.

In terms of transcriptomic analysis, although batch effects between the GSE and GTEx databases were corrected using the ComBat algorithm, and the comparability of the integrated data was verified through PCA, there remain certain differences in sample size and individual characteristics (such as BMI levels, gender composition, etc.), which may influence the robust identification of differentially expressed genes. Particularly in the exploration of mechanisms using cold-induced muscle shivering as a model for exercise intervention, while this model does not fully replicate the metabolic activation mechanisms of voluntary exercise, it offers a certain degree of substitutability in terms of controllability, ethical applicability, and biological energy mobilization. Therefore, it can serve as an approximate research tool to study the involvement of Vitamin D in skeletal muscle metabolic remodeling. It is also worth noting that some of the included studies did not provide detailed information on Vitamin D formulation, bioavailability, intervention duration, or adherence to supplementation, limiting the in-depth analysis of the dose–response relationship. Furthermore, the lack of baseline 25(OH)D status reports restricts the evaluation of sensitivity in Vitamin D deficiency subgroups. Future research should focus on intervention stratification based on individual nutritional status, particularly in individuals with low or deficient Vitamin D levels, by combining multimodal exercise interventions (i.e., composite regimens involving various types of exercise). This approach could enhance the comparability and external validity of intervention outcomes.

The clinical significance of this study lies in the finding that Vitamin D supplementation can amplify the weight loss effects induced by exercise, particularly in improving waist circumference and promoting reductions in weight and BMI. These benefits are especially pronounced in older adults and overweight or obese individuals undergoing aerobic exercise interventions. Our findings suggest that combining exercise with Vitamin D supplementation may represent an effective strategy for optimizing weight management and metabolic health. Therefore, future studies should further define the optimal exercise protocols, explore the ideal dosage and duration of Vitamin D supplementation, and examine its effects on other metabolic markers, such as blood glucose and lipid profiles, to enhance its clinical efficacy in improving body composition and metabolic health. Additionally, the integration of multi-omics data and nutritional behavior monitoring technologies to systematically elucidate the mechanisms underlying the combined effects of Vitamin D and exercise, as well as individual response differences, will provide stronger empirical support for the development of precise and effective exercise-nutrition combined interventions.

This study systematically evaluated the effects of Vitamin D supplementation on exercise-based interventions in overweight and obese adults, and explored potential underlying mechanisms using transcriptomic data. Transcriptomic analysis revealed that Vitamin D-related gene expression in skeletal muscle is significantly altered in individuals with obesity, primarily through pathways involving fat absorption, pancreatic function, calcium transport, and hormone metabolism. Additionally, a cold-induced muscle shivering model indicated significant enrichment of Vitamin D-responsive genes and their downstream pathways following intervention, suggesting a potential role in muscle metabolic regulation. Meta-analysis results showed that combining exercise with Vitamin D supplementation significantly improved waist circumference reduction, with more pronounced effects on weight and BMI observed in older adults and those engaging in aerobic training—supporting a possible synergistic effect. However, no significant enhancements were observed in glucose or lipid metabolism, which may be due to individual differences in Vitamin D metabolism, baseline levels, or intervention protocols. In summary, Vitamin D supplementation may enhance exercise-induced benefits by improving skeletal muscle metabolism and adaptive responses, thereby synergistically supporting weight-loss interventions. Future research should focus on personalized Vitamin D status, intervention intensity and duration, and molecular validation, aiming to develop more precise and effective nutrition-exercise strategies for overweight and obese populations.