Extended Abstract
Introduction
Vitamin D receptors are present throughout the human body, indicating the vitamin’s diverse functions. Since the body’s vitamin D is mostly the result of endogenous synthesis, it is often considered a hormone rather than a vitamin. Vitamin D deficiency affects numerous physiological systems and a broad range of health-related factors. Vitamin D deficiency is linked to depression and cognitive impairment, and both aging and increased body fat mass enhance the risk of vitamin D deficiency.
The association between vitamin D deficiency and obesity, as well as related diseases, has been confirmed in numerous studies. Obesity can be viewed as a risk factor for vitamin D deficiency status. Evidence suggests that engaging in physical activity (even in the absence of weight loss) may help release vitamin D from adipose tissue, which could improve the health of obese or overweight individuals or those with low circulating vitamin D levels. However, the effects of exercise interventions on inflammation and oxidative stress in the coexistence of vitamin D deficiency and obesity/overweight are not well understood. The present review aims to assess the role of vitamin D deficiency accompanied by obesity/overweight on the inflammatory-oxidative status and to investigate the effects of exercise on 25-hydroxyvitamin D levels and some mediating factors in inflammation and oxidative stress in vitamin D deficiency status accompanied by obesity/overweight.
Methods
In this systematic review, a comprehensive search for articles was conducted in both Persian and English languages from 2006 to 2023 in the specialized databases of PubMed, Scopus, and state inpatient database (SID).
Discussion
Synthesis of Vitamin D Metabolites: Vitamin D is primarily synthesized by the skin. In the epidermis, 7-dehydrocholesterol can be converted to vitamin D3 (cholecalciferol) upon exposure to sunlight. The synthesized vitamin D3 from the skin, as well as dietary or supplemental D2/D3, is catalyzed to 25-hydroxyvitamin D by the 25-hydroxylase enzyme (cytochrome P450 [CYP], CYP2R1, and CYP27A1 enzymes) in the liver. The 25-hydroxyvitamin D binds to the vitamin D binding protein and is transported in the bloodstream. The vitamin D binding protein is primarily synthesized and secreted by the liver.
The 1,25-dihydroxy vitamin D (calcitriol) is the principal and active metabolic form of vitamin D, produced in the kidney. It regulates physiological processes by binding to a vitamin D receptor, typically located in the nucleus of target cells.
Vitamin D Deficiency and Obesity: Obese individuals exhibit lower circulating concentrations of 25-hydroxyvitamin D compared to those with a normal weight.
Previous studies have reported lower vitamin D levels in obese and overweight individuals. With increased deposition of vitamin D in adipose tissue, serum vitamin D concentrations decrease in obesity status. Furthermore, lower concentrations of 25-hydroxyvitamin D have been demonstrated to be associated with a higher body mass index (BMI). These findings highlight a close relationship between vitamin D and adipose tissue, suggesting that obesity is linked to vitamin D deficiency. Additionally, the hepatic synthesis of 25-hydroxyvitamin D may occur in obese individuals more slowly due to hepatic steatosis. One potential explanation is that higher circulating levels of leptin and interleukin-6 (IL-6) (primarily secreted by adipose tissue) may exert inhibitory effects on the synthesis of 25-hydroxyvitamin D through their respective receptors. Conversely, lower levels of 25-hydroxyvitamin D can culminate in increased differentiation of preadipocytes into adipocytes, resulting in increased weight gain in obese individuals. Consequently, this can further contribute to the development of chronic low-grade inflammation and a heightened risk of obesity-related metabolic disorders.
The Effects of Exercise on Vitamin D Status: Over 90% of the vitamin D our bodies need is obtained from sun exposure. However, research indicates that both indoor and outdoor activities positively impact vitamin D status. Endurance exercises can significantly increase serum 25-hydroxyvitamin D levels in individuals with vitamin D deficiency; however, no significant effect on 25-hydroxyvitamin D levels has been observed in individuals with sufficient vitamin D, and this benefit has not been observed in resistance exercises. Physical activity may affect blood 25-hydroxyvitamin D levels by regulating vitamin D metabolites stored in target tissues, and these effects may depend on various factors, such as nutritional status, vitamin D status, type and intensity of exercise, and gender. One study indicated that 8 weeks of Pilates exercises was associated with a 16% increase in 25-hydroxyvitamin D levels in overweight middle-aged men with vitamin D deficiency. Additionally, an increase in 25-hydroxyvitamin D levels has been reported in overweight young women with vitamin D deficiency after 8 weeks of both resistance exercises and high-intensity running intervals or aerobic exercises in overweight diabetic patients. Furthermore, following 12 weeks of moderate-intensity aerobic exercises at 70% of maximum heart rate reserve, 25-hydroxyvitamin D levels increased significantly in postmenopausal women. During physical activity, concurrent with increased blood flow to adipose tissue, levels of lipolytic-stimulating hormones, such as adrenaline, glucagon, and atrial natriuretic peptide, increase, while plasma insulin concentrations decrease, which contributes to a strong increase in lipolysis. These processes culminate in the hydrolysis of triacylglycerol from fat cells by the adipose triglyceride lipase and hormone-sensitive lipase enzymes. With a two to three-fold increase in adipose tissue lipolysis induced by exercise in both fasting and non-fasting conditions, vitamin D metabolites may also be released from body fat cells. Additionally, it has been demonstrated that various exercise protocols (high-intensity running intervals, moderate-intensity continuous exercises, and sprint interval exercises) can enhance energy expenditure through post-exercise excessive oxygen consumption. The energy deficit due to exercise has strong effects on endogenous lipid metabolism, increasing triacylglycerol concentrations, and increasing the mobilization and oxidation of plasma fatty acids.
The Effects of Exercise on Oxidative Stress in Vitamin D Deficiency Status Accompanied by Obesity: Oxidative stress refers to an imbalance between oxidative and antioxidant systems, leading to an accumulation of reactive oxygen species (ROS). ROS are small, unstable, and highly reactive molecules that can oxidize proteins, lipids, and DNA. Oxidative stress occurs when the rate of ROS increase exceeds the capacity of antioxidants to neutralize them. Superoxide dismutases (SODs) are a critical antioxidant defense against oxidative stress. SOD analogs have been demonstrated to have anti-obesity effects at the molecular level by influencing metabolic pathways and associated enzymes. Under normal vitamin D status, a significant portion of intracellular related-oxidative stress processes are mitigated. However, at suboptimal levels of 25-hydroxyvitamin D, serum oxidative stress becomes resistant to antioxidant control, culminating in intracellular oxidative damage and accelerated apoptosis. In obesity status, elevated oxidative stress leads to a decrease in vitamin D binding protein and 25-hydroxylase, which can further reduce circulating 25-hydroxyvitamin D levels. Consequently, increasing vitamin D levels may be associated with improved antioxidant capacity.
The Effects of Exercise on Inflammatory Markers in Vitamin D Deficiency Status Accompanied by Obesity: In conditions of overweight and obesity, levels of inflammatory markers increase, which is likely due to increased production of pro-inflammatory cytokines from various tissues/cells, including macrophages in adipose tissue, vascular endothelial cells, and peripheral blood mononuclear cells. Based on the evidence, adipose tissue hypoxia may be a crucial mechanism through which enlarged adipose tissue causes local tissue inflammation and also increases systemic inflammation. Additionally, obesity-induced inflammation is often accompanied by increased oxidative stress. However, an increase in ROS or a decrease in antioxidant capacity, leading to oxidative stress, can disrupt adipose tissue function.
In obesity, vitamin D deficiency and inflammation often occur simultaneously; however, it is unclear whether low concentrations of vitamin D give rise to an exacerbation of the obesity-related inflammatory conditions. Inflammation can lead to increased oxidative catabolism of 25-hydroxyvitamin D through oxidative stress and, in an oxidative environment, disrupt the hepatic biosynthesis of 25-hydroxyvitamin D. Thus, inflammation can be associated with decreased levels of 25-hydroxyvitamin D. Furthermore, vitamin D can mitigate inflammation by improving the antioxidant status.
The Effects of Exercise on Chemokine Markers in Vitamin D Deficiency Status Accompanied by Obesity: Chemokines belong to a family of small cytokines with a molecular weight of 8 to 10 kDa, secreted by immune system cells. These proteins function as chemotactic cytokines, inducing directed migration of leukocytes following interaction with their specific receptors, a process known as chemotaxis. Monocyte chemoattractant protein-1 (MCP-1) and eotaxin are among the chemokines with pro-inflammatory properties. MCP-1 is expressed through oxidative stress and nuclear factor kappa B (NF-κB) activation. MCP-1 attracts monocytes to the site of inflammation in diseases. By activating its receptor and signaling pathways that induce cell migration, it plays a role in the progression of various disorders. Obesity is associated with induced hypoxia in white adipose tissue and, consequently, an increase in oxidative stress, resulting in impaired MCP-1 control and, as a result, upregulation of MCP-1. Eotaxin is a secretory product of adipose tissue and its levels increase in obesity. Vitamin D deficiency increases NF-κB expression, leading to increased secretion and release of MCP-1. The active form of vitamin D (1,25-dihydroxyvitamin D) can inhibit the recruitment of monocytes and preadipocytes to adipose tissue by inhibiting MCP-1 production. Vitamin D can also inhibit interleukin-1-beta (IL-1β)-induced eotaxin secretion. IL-1β is a cytokine with a wide range of pro-inflammatory functions involved in the recruitment of inflammatory cells to inflamed tissues, including adhesion to endothelial cells, transendothelial migration, and subsequent chemotactic movement. Therefore, reduced vitamin D levels in obese individuals may be one of the potential mechanisms for increased MCP-1 and eotaxin chemokines, which may be negatively regulated through exercise intervention. Exercise can lead to changes in adipose tissue phenotype by significantly reducing M1 macrophages (promoting inflammation) and increasing M2 macrophages (reducing inflammation and stimulating tissue repair), reducing inflammatory factors, and increasing anti-inflammatory indices as a result of reduced oxidative stress and inflammation.
Conclusion
Various types of exercise may improve vitamin D status through multiple mechanisms, including increased adipose tissue blood flow and levels of lipolytic stimulating factors, decreased plasma insulin, increased fatty acid oxidation and fat lipolysis, and oxidative catabolism of 25-hydroxyvitamin D. Additionally, the increased levels of 25-hydroxyvitamin D resulting from exercise can improve vitamin D status through other mechanisms such as reducing the vicious cycle of inflammation and oxidation in vitamin D deficiency status, due to its anti-inflammatory and antioxidant properties.

Key message: Regular physical exercise can improve vitamin D status in obese and overweight individuals.