Uncovering hidden vitamin D deficiency in overweight children

Abstract

Vitamin D deficiency is disproportionately prevalent among overweight and obese children, with conventional explanations such as poor dietary intake or reduced sun exposure offering only partial insight. Emerging evidence reveals a multifactorial pathophysiology, including sequestration of vitamin D in adipose tissue, altered hepatic metabolism, diminished bioavailability, and inflammation-induced resistance at the tissue level. These mechanisms contribute to a functional deficiency, wherein serum 25-hydroxyvitamin D levels may remain suboptimal despite adequate intake or sun exposure. Obesity-related alterations in vitamin D-binding proteins, receptor expression, and pro-inflammatory signaling further compromise biological activity. Current diagnostic criteria and supplementation guidelines do not fully reflect these physiological complexities, leading to underdiagnosis and insufficient treatment. Personalized approaches-incorporating higher, body composition-adjusted dosing and consideration of inflammatory status-are emerging as promising strategies to restore sufficiency and improve metabolic outcomes. While preliminary evidence supports the safety and efficacy of high-dose supplementation in this population, pediatric-specific clinical trials are lacking. This review synthesizes current understanding of the pathophysiological mechanisms underlying vitamin D deficiency in pediatric obesity and emphasizes the need for individualized, evidence-based interventions to optimize vitamin D status and overall health.

Key Words: Vitamin D deficiency; Pediatric obesity; Adipose sequestration; 25-hydroxyvitamin D; Bioavailability; Vitamin D metabolism; High-dose supplementation

Core Tip: This review challenges the conventional understanding of vitamin D deficiency in children with obesity by proposing a mechanistic framework that integrates adipose tissue dynamics, hepatic metabolism, and inflammatory signaling. It emphasizes that vitamin D status is not solely determined by intake or sun exposure, but rather results from complex physiological interactions. By highlighting the limitations of current diagnostic thresholds and supplementation strategies, the study advocates for a paradigm shift toward individualized, mechanism-based treatment approaches-an essential step to bridge the gap between biochemical adequacy and functional sufficiency in this vulnerable population.

INTRODUCTION

This review addresses the emerging concept of functional vitamin D deficiency in overweight and obese children, highlighting its multifactorial pathophysiology, diagnostic challenges, and implications for individualized treatment strategies.

Vitamin D deficiency in children is a growing concern globally. While it is traditionally attributed to insufficient intake or inadequate sun exposure, emerging evidence reveals a more nuanced pathophysiological mechanism in overweight and obese children: Functional deficiency due to vitamin D sequestration in adipose tissue[1]. In the context of rising pediatric obesity rates, this subtler and often overlooked form of deficiency becomes increasingly relevant. Vitamin D deficiency affects approximately 40%-50% of obese children in the United States, with global estimates reaching up to 60%, particularly in urban areas and during seasons with limited sunlight exposure[2]. Similarly high rates have been observed in parts of Europe, China, and among immigrant populations in Northern latitudes[3]. Despite adequate intake and sun exposure, many overweight and obese children maintain suboptimal 25-hydroxyvitamin D [25(OH)D] levels[4]. Physical inactivity, often associated with obesity, may further exacerbate low vitamin D levels due to less outdoor time and decreased sun exposure[5]. A recent review by Devulapalli discusses the dual role of physical activity and vitamin D in shaping bone health and fitness in children, emphasizing the importance of outdoor activity in both obesity prevention and micronutrient status[5]. By elucidating the biological mechanisms behind this paradoxical deficiency and reviewing tailored therapeutic approaches, this paper aims to inform evidence-based clinical care for this at-risk population.

ADIPOSE SEQUESTRATION AND FUNCTIONAL DEFICIENCY

Vitamin D is lipophilic and readily stored in adipose tissue. In children with obesity, an increased volume of fat serves as a reservoir, sequestering vitamin D and reducing its bioavailability in circulation. This leads to a functional deficiency, where vitamin D is present in the body but not accessible for physiological functions. Even with similar synthesis in the skin after ultraviolet B exposure, obese individuals demonstrate smaller increases in serum vitamin D levels than their lean counterparts[1]. Holmlund-Suila et al[6] demonstrated that standard supplementation in infants may not achieve optimal levels without adjusting for body size. This suggests that volume of distribution and sequestration significantly impact efficacy. Turer et al[2] also reported an inverse correlation between body mass index (BMI) and 25(OH)D levels in a nationally representative sample of United States children. Similar findings were noted by Smotkin-Tangorra et al[7], who found low vitamin D levels in overweight adolescents independent of season or ethnicity. Studies in children also suggest that increased fat mass may impair mobilization of vitamin D from adipose stores into circulation, possibly through changes in lipid droplet dynamics and storage protein interactions[8,9].

ALTERED VITAMIN D METABOLISM AND BIOAVAILABILITY

Beyond sequestration in adipose tissue, obesity-related changes in vitamin D metabolism further contribute to deficiency (Table 1). Roizen et al[10] showed that obesity decreases hepatic 25-hydroxylase activity, leading to significantly lower 25(OH)D levels despite similar intake. Non-alcoholic fatty liver disease, common among overweight children, may impair hepatic 25-hydroxylation, the critical step converting vitamin D into its circulating form, 25(OH)D[10]. Additionally, inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6, elevated in adiposity, can downregulate hepatic enzymes like cytochrome P450 2R1 (CYP2R1), further limiting 25(OH)D production[10]. The kidneys’ conversion of 25(OH)D to its active form, calcitriol, may also be affected indirectly by altered parathyroid hormone levels arising from relative hypocalcemia. Furthermore, most circulating vitamin D is bound to vitamin D-binding protein (DBP), which regulates its transport and availability to tissues. Obesity may alter DBP concentrations or binding affinities, changing the proportion of free, bioavailable vitamin D not detected by standard total 25(OH)D assays[11,12]. Powe et al[11] highlighted racial differences in DBP and the implications for assessing true vitamin D sufficiency in diverse pediatric populations. These metabolic and transport alterations underscore the complex regulation of vitamin D status in overweight children, beyond simple serum concentration measurements.

Table 1 Mechanisms of functional vitamin D deficiency in pediatric obesity.

Mechanism (Ref.)	Description	Clinical implications
Adipose sequestration[1,2,6-9]	Vitamin D accumulates in adipose tissue, reducing its availability in circulation	Standard supplementation may be inadequate; requires higher doses for efficacy
Expanded volume of distribution[2,6]	Larger fat mass dilutes serum vitamin D levels	Dose adjustments based on body size or surface area may be necessary
Impaired hepatic 25-hydroxylation[9,10]	Obesity and non-alcoholic liver disease reduce conversion of vitamin D to 25(OH)D	Liver dysfunction must be considered when interpreting low 25(OH)D levels; supplementation may need to be higher or targeted
Inflammation-induced enzyme inhibition[10]	Cytokines downregulate CYP2R1 and related enzymes	Chronic inflammation may impair conversion; treating underlying inflammation may improve vitamin D status
Altered vitamin D-binding protein[11,12]	Obesity may affect DBP levels or affinity, reducing free vitamin D	Standard total 25(OH)D assays may underestimate deficiency; measurement of free or bioavailable vitamin D should be considered
Reduced vitamin D receptor expression/function[13-15]	Obesity-related inflammation may downregulate receptors or impair downstream signaling	May explain symptoms despite adequate serum levels; supports use of functional endpoints in assessing sufficiency
Epigenetic and intracellular alterations[16,17,19]	Obesity may induce VDR resistance via epigenetic and intracellular signaling changes	Emerging concept; may require future biomarker development to detect tissue-level deficiency or resistance

25(OH)D: 25-hydroxyvitamin D; DBP: Vitamin D-binding protein; CYP2R1: Cytochrome P450 2R1; VDR: Vitamin D receptor.

POLYMORHISMS AFFECTING VITAMIN D IN OBESITY

Genetic polymorphisms may contribute to altered vitamin D status in obese children, beyond environmental and dietary factors (Table 1). Beyond availability, vitamin D responsiveness may be diminished in obesity due to altered expression or function of vitamin D receptors (VDRs). VDR polymorphisms, such as TaqI, BsmI, and FokI, have been associated with both obesity and vitamin D deficiency in children, possibly affecting receptor function and downstream signaling[13,14]. A literature review reported that 48 out of 57 gene-obesity associations involved VDR single nucleotide polymorphisms[13]. In a recent study of children, polymorphisms in VDR and CYP2R1 were found to influence BMI independently of serum 25(OH)D concentrations, highlighting a potential genetic contribution to body weight regulation beyond vitamin D status[15].

Variants in the GC gene encoding DBP influence bioavailability; a 2021 Turkish study found obese children had lower free and bioavailable vitamin D, despite similar total 25(OH)D, partly due to elevated DBP and its polymorphisms[16]. A 2022 randomized controlled trial (RCT) showed that the rs2282679 variant in GC modulated responses to vitamin D supplementation in overweight youth, with minor-allele carriers achieving lower serum increases[17].

Chronic low-grade inflammation and metabolic dysregulation may lead to downregulation of VDRs or impair receptor signaling pathways. This concept of tissue-level vitamin D resistance, although still under investigation, may help explain persistent clinical deficiency symptoms in the face of adequate or mildly low serum 25(OH)D levels[18]. Emerging evidence suggests that epigenetic modifications and altered intracellular signaling in obesity could contribute to impaired VDR function, highlighting a multifaceted disruption of vitamin D action at the molecular level[19].

CLINICAL IMPLICATIONS AND FUTURE DIRECTIONS

Current vitamin D intake guidelines do not account for variations in body composition, which may partly explain why standard supplementation often fails to normalize serum levels in obese children. Studies indicate that higher or individualized doses-adjusted for BMI, surface area, or fat distribution-are often necessary to overcome adipose sequestration and altered metabolism[6,20]. Clinicians should also consider inflammation, hepatic function, and levels of free or bioavailable vitamin D when assessing deficiency, as these factors can markedly affect therapeutic response. Moreover, emerging data indicate that addressing vitamin D deficiency in obese children may have benefits beyond bone health, potentially improving insulin resistance, immune function, and inflammation-related outcomes[21]. In a randomized clinical trial, Rajakumar et al[22] demonstrated that vitamin D3 supplementation in deficient overweight and obese children improved insulin sensitivity and metabolic parameters, supporting these broader health benefits.

Only a limited number of randomized trials have investigated high-dose vitamin D supplementation in obese children, and even fewer have assessed functional outcomes beyond serum 25(OH)D concentrations[23]. Although the concept of individualized dosing is increasingly recognized, its application in pediatric clinical practice remains inconsistent due to the lack of specific guidelines. Some RCTs suggest potential benefits of tailored strategies: For example, Kelishadi et al[24] reported that high-dose cholecalciferol improved both serum vitamin D levels and insulin sensitivity in obese children, supporting the feasibility of such approaches. In contrast, Brzeziński et al[25] demonstrated that supplementation with 1200 IU/day was safe and effective in correcting vitamin D deficiency during a structured weight-loss program, but it did not confer additional benefits on weight reduction or metabolic parameters beyond those achieved through the lifestyle intervention itself.

High-dose vitamin D supplementation has shown potential in improving metabolic parameters in this population. A systematic review by Corsello et al[23] found modest increases in 25(OH)D across 23 trials, though effects on cardiometabolic outcomes varied. A network meta-analysis showed that daily doses exceeding 4000 IU led to significant improvements in HOMA-IR and inflammatory markers such as C-reactive protein[26]. In a triple-masked RCT, a loading dose of 300000 IU over 12 weeks yielded substantial improvements in insulin resistance and metabolic syndrome scores[24]. Similarly, a 6-month trial using 4000 IU/day in adolescents led to marked gains in insulin sensitivity and leptin/adiponectin ratios[27].

Future research should define optimal reference ranges for bioavailable vitamin D in pediatric obesity and improve assays for measuring free vitamin D. Additionally, studies exploring genetic variants and long-term functional outcomes of personalized supplementation are needed to guide clinical care.

CONCLUSION

Vitamin D deficiency in overweight and obese children is not simply a result of inadequate intake or limited sun exposure, but a complex, functional disruption influenced by adipose tissue sequestration, altered metabolism, and reduced bioavailability. Standard diagnostic and treatment approaches often fail to account for these physiological differences, resulting in under recognition and suboptimal care. As pediatric obesity continues to rise globally, it is essential to understand and address the unique mechanisms affecting vitamin D status in this population. Individualized strategies that integrate body composition, inflammation, and metabolic context offer a more effective approach to correction. Advancing this targeted perspective will be key to improving not only vitamin D sufficiency but broader metabolic and immune health in affected children.