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Vitamin D and obesity: current perspectives and future directions

Published online by Cambridge University Press:  31 October 2014

L. Kirsty Pourshahidi
L. Kirsty Pourshahidi*
Affiliation:
Northern Ireland Centre for Food and Health, University of Ulster, Coleraine BT52 1SA, UK
*
Corresponding author: Dr K. Pourshahidi, fax +44(0)2870123023, email k.pourshahidi@ulster.ac.uk
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Abstract

In recent years, new functional roles of vitamin D beyond its traditional role in calcium homoeostasis and bone metabolism have emerged linking the fat-soluble vitamin to various non-communicable diseases. Vitamin D deficiency (25-hydroxyvitamin D (25(OH)D) < 25–30 nmol/l) and sub-optimal status (25(OH)D < 50–100 nmol/l) are increasingly associated with unfavourable metabolic phenotypes, including insulin resistance, type 2 diabetes and CVD; conditions also commonly linked with overweight and obesity. Early studies reported poor vitamin D status in the morbidly obese. More recently, it has been observed that a graded relationship between vitamin D status and BMI, or specifically adiposity, exists in the general population. A number of hypotheses have been proposed to explain the potential mechanisms whereby alterations in the vitamin D endocrine system occur in the obese state. Plausible explanations include sequestration in adipose tissue, volumetric dilution or negative feedback mechanisms from increased circulating 1,25-dihydroxyvitamin D3. Others hypothesise that heavier individuals may partake in less outdoor activity, may also cover-up and wear more clothing than leaner individuals, thus decreasing sun exposure and limiting endogenous production of cholecalciferol in the skin. Moreover, in some but not all studies, BMI and adiposity have been negatively associated with the change in vitamin D status following vitamin D supplementation. It therefore remains unclear if body size and/or adiposity should be taken into account when determining the dietary requirements for vitamin D. This review will evaluate the current evidence linking vitamin D status and supplementation to overweight and obesity, and discuss the implications for setting dietary requirements.

Keywords

Vitamin DObesityBMIFat massAdipose tissue
Type
Conference on ‘Changing dietary behaviour: physiology through to practice’
Information
Proceedings of the Nutrition Society , Volume 74 , Issue 2 , May 2015 , pp. 115 - 124
Copyright
Copyright © The Authors 2014 

Traditional roles of vitamin D lie within the musculoskeletal system, maintaining calcium homoeostasis and bone metabolism, with deficiency leading to conditions such as rickets in children, or osteoporosis and osteomalacia in adults( Reference Suda, Ueno and Fujii 1 ). However, obesity is now frequently cited as a cause of vitamin D deficiency( Reference Holick 2 , Reference Kaidar-Person, Person and Szomstein 3 ), which may in fact lead to other co-morbidities, such as diabetes and CVD, conditions commonly linked to obesity( Reference Holick 4 , Reference Schottker, Haug and Schomburg 5 ).

Indeed, obesity and vitamin D deficiency have concomitantly reached epidemic levels worldwide and research linking the two has grown extensively over the last number of years. It is reasonable to suggest that this nutritional inadequacy may be driven by the increasing obesity rates within the general population, and may therefore improve with a reversal of the latter. However, despite the plethora of evidence available, the mechanisms remain largely unclear and the area of reverse causality is also commonly debated within the literature: does obesity lead to vitamin D deficiency or vice versa?

Vitamin D is not technically a vitamin, but is better classified as an active circulating pre-hormone within the body. Limited amounts of vitamin D are obtained from dietary sources such as oily fish, liver and fortified foods, such as milks, breakfast cereals and margarines, or dietary supplements. However, the main source is through cutaneous production via the action of UVB irradiation (wavelength 290–315 nm) which converts 7-dehydrocholesterol to previtamin D3 in the epidermis of the skin( Reference MacLaughlin, Anderson and Holick 6 , Reference Webb and Holick 7 ). Hydroxylation in the liver results in the formation of 25-hydroxyvitamin D3 (25(OH)D), the status measure of the vitamin, which makes up our stores of the vitamin and being fat-soluble, this storage is mainly in the adipose (fat) tissue( Reference Rosenstreich, Rich and Volwiler 8 , Reference Mawer, Backhouse and Holman 9 ). When required by the body, a further hydroxylation step forms the biologically active form of the vitamin, 1,25-dihydroxyvitamin D3 (1,25(OH)D), which exerts its actions in vivo via the vitamin D receptor (VDR). As the endogenous production of vitamin D only occurs at a particular sunlight intensity, usually only during the summer months at high latitudes (approximately April–September), this typically gives rise to seasonal variations in vitamin D status throughout the year( Reference MacLaughlin, Anderson and Holick 6 , Reference Webb and Holick 7 ).

Over the course of human evolution, we have developed a more cutaneous phenotype, with depigmented skin manifesting with migration away from the equator( Reference Jablonski and Chaplin 10 , Reference Yuen and Jablonski 11 ). The adaptation of a more vitamin D-rich diet, as well as genetic modifications have also been reported with such migration, to further enhance our vitamin D intake from both diet and the sun( Reference Kuan, Martineau and Griffiths 12 , Reference Chaplin and Jablonski 13 ). Unfortunately this ‘vitamin D compromise’ that has occurred over the course of evolution may now have been broken in today's modern and westernised lifestyles, with increasing obesity rates and more sedentary/indoor lifestyles.

The aims of the present review were to evaluate the current evidence linking vitamin D status and supplementation to overweight and obesity, and discuss the potential implications for setting dietary requirements.

Vitamin D and obesity

Commonly suggested mechanisms

There are four suggested mechanisms that are most commonly cited within the literature which may explain a low vitamin D status in obesity: (1) obese individuals have decreased sun exposure compared with their lean counterparts; (2) negative feedback from an increased 1,25(OH)D concentration in obese individuals decreases 25(OH)D concentrations; (3) vitamin D is sequestered within adipose tissue; (4) lower 25(OH)D concentration is simply due to volumetric dilution.

Decreased sun exposure

While a decreased sun exposure may initially seem counterintuitive because of the larger body surface area in obesity that is available for endogenous synthesis( Reference Verbraecken, Van de Heyning and De Backer 14 ), obese individuals reportedly have a limited mobility, they may avoid outdoor activity and may cover-up more when outdoors compared with their lean or normal-weight counterparts( Reference Compston, Vedi and Ledger 15 – Reference Vanlint 17 ). Solid evidence for this theory is lacking and may be mainly anecdotal, and although, for example, there may be some evidence that obese individuals partake in less physical activity( Reference Petersen, Schnohr and Sorensen 18 , Reference Atienza, Yaroch and Masse 19 ), levels of outdoor physical activity are often not specified so it is difficult to draw definitive conclusions on the subsequent effect on vitamin D status.

Negative feedback from 1,25-dihydroxyvitamin D3

Evidence for the negative feedback from increased circulating 1,25(OH)D concentrations in obesity is equivocal. As introduced earlier, when required by the body, 25(OH)D is further hydroxylated to form the active metabolite, 1,25(OH)D, which in turn ‘switches off’ the production of 25(OH)D. Indeed, increased 1,25(OH)D, and therefore decreased 25(OH)D concentration, in obese compared with non-obese subjects was reported in earlier smaller studies( Reference Hey, Stokholm and Lund 20 , Reference Bell, Epstein and Greene 21 ), but more recently, larger studies show the opposite is true( Reference Parikh, Edelman and Uwaifo 22 – Reference Lagunova, Porojnicu and Vieth 25 ). Data supporting this mechanism remain inconclusive.

Sequestration in adipose tissue

The study of Wortsman et al. ( Reference Wortsman, Matsuoka and Chen 26 ) was the first to provide strong, convincing evidence that vitamin D (as a fat-soluble vitamin), may become sequestered (i.e. trapped or hidden) within adipose tissue. In their study, nineteen lean and nineteen obese individuals (BMI ≤ 25 and >30 kg/m2, respectively) were exposed to UVB irradiation for 24 h. The concentration of circulating cholecalciferol was similar between the groups at baseline, but the obese group had a significantly blunted response to the UVB intervention, resulting in a 57 % lower serum cholecalciferol concentration post-intervention, compared with the control (lean) group. Adding support to their theory was the fact that both obese and control groups had similar levels of 7-dehydrocholesterol available in the skin prior to intervention. This suggested that the limitation in the obese group was the bioavailability of the synthesised cholecalciferol in circulation( Reference Wortsman, Matsuoka and Chen 26 ). This sequestration theory is probably the most supported within the literature and others have since quantified that obese children and adults require 2–5 times more vitamin D to prevent or treat deficiency compared with their lean counterparts, because of such sequestration in adipose tissue( Reference Hossein-nezhad and Holick 27 ).

The cholecalciferol content of adipose tissue has been quantified( Reference Lawson, Douglas and Lean 28 – Reference Malmberg, Karlsson and Svensson 30 ) and is positively correlated with serum 25(OH)D concentrations in obese subjects( Reference Blum, Dolnikowski and Seyoum 29 ). In a recent pilot study of six females, a significantly lower cholecalciferol and 25(OH)D (but not 1,25(OH)D) content of subcutaneous adipose tissue was observed in obese compared with lean individuals( Reference Malmberg, Karlsson and Svensson 30 ). Although these data appear to question the sequestration theory suggested by Wortsman et al. ( Reference Wortsman, Matsuoka and Chen 26 ), further evidence on the bioavailability of vitamin D from adipose tissue in overweight/obese individuals is required from larger studies (including males and females) before definitive conclusions can be drawn.

Volumetric dilution

Most recently, other convincing data suggest that it is simply volumetric dilution that explains the low vitamin D status of obesity, i.e. putting the same amount into a larger pool, will result in a lower concentration. Drincic et al. ( Reference Drincic, Armas and Van Diest 31 ) showed that the inverse relationship between serum 25(OH)D concentration and body weight was apparent in 686 healthy adults taking minimal supplemental doses of vitamin D (<10 μg/d). Of interest though, in their hyperbolic model (the mathematical expression of dilution), when adjusted for body size, the difference in 25(OH)D concentrations between normal-weight and obese individuals was removed. These authors went on to recommend that the vitamin D dosing regimen for treatment of vitamin D deficiency in obesity should be based on body weight, i.e. ‘one size does not fit all’( Reference Drincic, Armas and Van Diest 31 ).

Overall, although these are the four most commonly suggested mechanisms, evidence for the former two is much weaker than that for the latter two theories, where robust evidence is available. Measuring sun exposure in the free-living setting can be problematic and therefore researchers usually rely on more subjective, self-reported measures. Similarly, concentrations of 1,25(OH)D are reported much less frequently within the literature given the relatively short half-life of this active metabolite, its tight metabolic regulation, and the fact that 25(OH)D has been widely accepted as the status measure of the vitamin( 32 ). Taken together, this may contribute to the lack of data supporting the effect of both factors on vitamin D status in obesity.

In contrast, the strong evidence presented earlier for the sequestration( Reference Wortsman, Matsuoka and Chen 26 ) and volumetric dilution( Reference Drincic, Armas and Van Diest 31 ) hypotheses, and more importantly, a lack of contradictory evidence for either, suggest that they are the most probable, either independently or in combination, to explain the low vitamin D status widely reported in overweight and obesity.

Observational evidence

Observational evidence linking vitamin D and obesity stems from the late 1970s when 25(OH)D concentrations were reported to be lower in morbidly obese patients v. controls both before and after gastric bypass surgery( Reference Hey, Stokholm and Lund 20 , Reference Teitelbaum, Halverson and Bates 33 ). In these studies, abnormalities in vitamin D metabolism following surgery were attributed to both post-operative complications (e.g. reduced gastric or intestinal absorption) as well as a reduced sun exposure during the recovery period. In the following few years, this was confirmed by other studies( Reference Compston, Vedi and Ledger 15 , Reference Bell, Epstein and Greene 21 , Reference Rickers, Christiansen and Balslev 34 – Reference Buffington, Walker and Cowan 36 ), one of which was the first to suggest that secondary hyperparathyroidism may also be contributing to vitamin D deficiency, as they observed significantly higher parathyroid hormone and 1,25(OH)D concentrations in the obese v. non-obese group( Reference Bell, Epstein and Greene 21 ). More recently in support of these findings, a systematic review has quantified that vitamin D deficiencies are critical after obesity surgery and are common in up to two-thirds of cases( Reference Stein, Stier and Raab 37 ). Vitamin D supplementation in such patient groups is successful in treating vitamin D deficiency( Reference Flores, Moize and Ortega 38 ) and should be prescribed, or at least recommended to patients, both before and after obesity surgery.

Using baseline data from two randomised, placebo-controlled vitamin D intervention studies, the association between body composition and 25(OH)D concentrations was investigated by the author in both young (age 20–40 years) and older (age ≥64 years) apparently healthy adults. These studies were originally designed to investigate the dietary requirements for vitamin D over the winter months (October–March) and full details have been previously published elsewhere( Reference Cashman, Hill and Lucey 39 , Reference Cashman, Wallace and Horigan 40 ). A benefit of this data was that baseline measures were all taken at the end of summer (i.e. when vitamin D status is expected to be at its peak) and therefore the confounding effect of seasonality on 25(OH)D concentrations was removed. In addition, measures of body composition included both the proxy measure of BMI as well as a more robust measure of fat mass (FM); four-site skinfold thickness measurements. Fig. 1 shows the association between 25(OH)D, BMI and FM in younger and older adults. Although in both age groups an inverse trend is apparent, this is only statistically significant in the older adults, with those in the obese category (BMI > 30 kg/m2) having a significantly lower vitamin D status compared with the healthy and overweight individuals (BMI < 25·0 and ≥ 25·0 kg/m2, respectively). A similar pattern was apparent when tertiles of FM were explored, again only significant in the older individuals, in that those with highest levels of FM had the lowest vitamin D status. Of interest within this study, sun exposure habits and levels of outdoor activity could also be compared between the BMI and FM groups and this did not appear to explain the difference in vitamin D status observed (LK Pourshahidi, MBE Livingstone and JMW Wallace, unpublished results). Although this may have suggested that sequestration in adipose tissue and/or volumetric dilution are most likely causes of the reported associations, data on sun exposure and physical activity were self-reported, and therefore should be interpreted with caution.

Fig. 1. Association between mean (±1 se) serum 25-hydroxyvitamin D (25(OH)D) and (a) BMI categories, (b) tertiles of fat mass in apparently healthy adults aged 20–40 years (n 236) and ≥64 years (n 207). Based on data derived from Cashman et al.( Reference Cashman, Hill and Lucey 39 , Reference Cashman, Wallace and Horigan 40 ) and Forsythe et al.( Reference Forsythe, Livingstone and Barnes 41 ). BMI categories: healthy weight, BMI ≤ 24·9 kg/m2; Overweight, BMI 25·0–29·9 kg/m2; Obese, BMI ≥ 30·0 kg/m2. P-value denotes significance between groups from ANOVA. Bars with different letters are significantly different within that age-group (Tukey post hoc tests, P < 0·05).

These findings have been extended and confirmed by many studies and a plethora of evidence now supports the association between overweight and/or obesity and vitamin D deficiency across all groups of the general population (children to very elderly), including evidence from large cohort studies such as the 1958 British Birth cohort( Reference Hypponen and Power 42 ) and the National Health and Nutrition Examination Survey( Reference Samuel and Borrell 43 ). However, the issue of reverse causality still remains, with some reporting that vitamin D deficiency is the cause of obesity( Reference Foss 44 ), and others suggesting that it is a new form of malnutrition within morbidly obese patients( Reference Kaidar-Person, Person and Szomstein 3 ). Recent evidence from a systematic review and meta-analysis have supported the significant inverse (albeit weak) correlation between 25(OH)D and BMI in adults (4 % reduction in 25(OH)D per each 10 % increase in BMI (P = 0·005))( Reference Saneei, Salehi-Abargouei and Esmaillzadeh 45 ). Using a bi-directional genetic approach, others confirm that it is high BMI, which leads to a lower 25(OH)D concentration, and any evidence for the reverse being smaller in effect( Reference Vimaleswaran, Berry and Lu 46 ). The same authors also report that vitamin D pathway genes are unlikely to play any role in obesity-related traits( Reference Vimaleswaran, Cavadino and Berry 47 ).

Notwithstanding the consistent association shown between overweight and obesity and low vitamin D status, it is noteworthy that the overall strength of the association is usually weak, which is most likely attributable to the significant heterogeneity between studies. This is at least partly owing to a number of methodological differences between studies which can have an impact on both vitamin D synthesis and status. Studies have been conducted worldwide at different latitudes, and many fail to account for seasonality or time of year within their analysis. Furthermore, data from different age and ethnic groups also adds to this heterogeneity as both ageing and skin colour can impact upon vitamin D synthesis and status, as well as body composition. Finally, analytical differences also make the comparison between studies difficult, as for both the assessment of body composition and vitamin D status, studies have used not only different methodologies but have also applied different cut-offs and classifications: both of which are a common debate within the literature.

Despite these limitations, the consistent inverse relationship between vitamin D and obesity is apparent from observational studies; however, by design, these studies cannot prove causality, and researchers began to ask the question, can an improvement in vitamin D status lead to weight loss or alternatively, a prevention of weight gain?

Prospective and intervention studies

Research has shown that the VDR is present in adipocytes (i.e. cells of the adipose tissue), which suggests that vitamin D does in fact play a role in modulating this active metabolic tissue( Reference Ding, Gao and Wilding 48 , Reference Mutt, Hypponen and Saarnio 49 ). Evidence suggests that 1,25(OH)D plays a central role in adipocyte metabolism via the inhibition of adipogenesis, independently of parathyroid hormone concentrations( Reference Narvaez, Matthews and Broun 50 , Reference Soares, Chan She Ping-Delfos and Ghanbari 51 ); with lower vitamin D stores potentially increasing the differentiation of pre-adipocytes to adipocytes (i.e. adipocyte growth)( Reference Soares, Chan She Ping-Delfos and Ghanbari 51 , Reference Nimitphong, Holick and Fried 52 ). Indeed 25(OH)D has been negatively associated with adipocyte size, albeit only in women to date( Reference Caron-Jobin, Morisset and Tremblay 53 ) and promising evidence from animal models also supports a protective role for vitamin D in the onset of diet-induced obesity by enhanced fatty acid oxidation( Reference Marcotorchino, Tourniaire and Astier 54 ) or increased adipose tissue apoptosis( Reference Sergeev and Song 55 ).

Secondary analysis of the Women's Health Initiative study concluded that calcium and vitamin D3 given in combination decreased the risk of postmenopausal weight gain over an average of 7 years( Reference Caan, Neuhouser and Aragaki 56 ) and other prospective studies have shown that weight loss can facilitate an increase in circulating 25(OH)D concentrations over time( Reference Rock, Emond and Flatt 57 – Reference Mason, Xiao and Imayama 60 ). Although this evidence appears promising in support of the relationship between vitamin D and weight loss, evidence from intervention studies is less clear( Reference Sneve, Figenschau and Jorde 61 – Reference Pathak, Soares and Calton 65 ). Many of these studies give cholecalciferol with or without calcium and show equivocal results. Furthermore, when calcium is given with cholecalciferol, the effects of the vitamin per se cannot be distinguished and the evidence from interventions where cholecalciferol is given alone is limited( Reference Soares, Chan She Ping-Delfos and Ghanbari 51 ).

Overall, the data does not consistently support the role of vitamin D (with or without calcium) in weight or FM loss. It also still remains unclear whether vitamin D acts directly by improving insulin sensitivity to facilitate weight loss, or indirectly through increased calcium absorption from the gut and suppression of circulating parathyroid hormone concentrations( Reference Soares, Murhadi and Kurpad 66 ). A more recent genetic study suggests that VDR target genes may predict individuals who will not respond to supplementation( Reference Ryynanen, Neme and Tuomainen 67 ), and inclusion of such individuals in intervention studies may contribute to the equivocal findings presented earlier. Further randomised controlled trials are required to address these current gaps within the literature.

Obesity, inflammation and 25-hydroxyvitamin D

Obesity is now widely recognised as a state of chronic, low-grade systemic inflammation( Reference Zhang, Proenca and Maffei 68 – Reference Ahima and Flier 70 ), with adipocytes shown to actively secrete a number of inflammatory molecules, including both pro- and anti-inflammatory cytokines, hormones, and acute phase reactants, such as C-reactive protein( Reference Zhang, Proenca and Maffei 68 , Reference Hotamisligil, Arner and Caro 71 – Reference Yudkin, Stehouwer and Emeis 74 ). Within the adipose tissue, other cells are also present including preadipocytes, mast cells and macrophages( Reference Weisberg, McCann and Desai 75 , Reference Xu, Barnes and Yang 76 ), which also contribute to this inflammatory milieu( Reference Frayn 77 , Reference Fain 78 ).

Extensive evidence has demonstrated that adipocytes become enlarged and dysregulated following weight gain, which subsequently produces an imbalance in the inflammatory profile of adipose tissue. Overweight and obesity are commonly linked to an up-regulation of pro-inflammatory molecules, and down-regulation of anti-inflammatory molecules, and this finding has been extensively reviewed( Reference Trayhurn and Wood 79 – Reference Galic, Oakhill and Steinberg 83 ). Moreover, others have shown that levels of obesity-related inflammatory markers can be improved with weight loss( Reference Dietrich and Jialal 84 – Reference Forsythe, Wallace and Livingstone 87 ).

Vitamin D has been reported to act as an acute phase reactant as a consequence of such an inflammatory response (e.g. in obesity) which can suppress the concentration of 25(OH)D( Reference Louw, Werbeck and Louw 88 , Reference Waldron, Ashby and Cornes 89 ). Polymorphisms affecting the VDR may also play a role in obesity, which may be partly mediated by ongoing inflammation( Reference Al-Daghri, Guerini and Al-Attas 90 ). Indeed, vitamin D has been positively correlated with the protective hormone adiponectin in obese individuals( Reference Edita, Aleksandar and Dragana 91 ) and an improvement in 25(OH)D concentrations has been reported to enhance the beneficial effects of weight loss, which may be at least partly owing to the anti-inflammatory effect of vitamin D( Reference Zittermann, Frisch and Berthold 62 , Reference Ghashut, Talwar and Kinsella 92 ). Data from metabolically healthy but obese (MHO) individuals add further support to this hypothesis. Individuals that present with the MHO phenotype, despite having a high FM, have a healthier metabolic profile compared with the typical metabolically unhealthy obese( Reference Karelis 93 ). Although a number of different definitions exist, MHO individuals commonly have higher insulin sensitivity and low inflammation for example, compared with the metabolically unhealthy obese group( Reference Karelis 93 – Reference Primeau, Coderre and Karelis 95 ). Recently it has been suggested that vitamin D may offer a protective metabolic effect in the MHO group( Reference Karelis and Rabasa-Lhoret 96 ). In a group of 4391 obese adults, Esteghamati et al. ( Reference Esteghamati, Aryan and Esteghamati 97 ) clearly demonstrated that, irrespective of the definition used to define MHO, 25(OH)D concentrations were significantly higher in the MHO individuals compared with the metabolically unhealthy obese group. Further research is warranted to confirm this finding and elucidate the anti-inflammatory or other underlying mechanisms to explain vitamin D's apparent protective metabolic effect in this unique subgroup of obese individuals.

Effect of obesity on the response to supplementation

It has long been recognised that the response to vitamin D supplementation is dependent on baseline 25(OH)D concentrations, i.e. those with a higher vitamin D status display an attenuated response compared with those with the lowest status( Reference Hossein-nezhad and Holick 27 , Reference Brannon, Yetley and Bailey 98 ). However, given the decreased bioavailability of vitamin D in obesity, and the purported effect of volumetric dilution discussed earlier( Reference Wortsman, Matsuoka and Chen 26 , Reference Drincic, Armas and Van Diest 31 ), it is reasonable to assume that the typical response to supplementation may be different in overweight/obese individuals, albeit that they are usually starting from a lower baseline value.

Table 1 shows nine studies, which have tested the hypothesis that adiposity can attenuate the 25(OH)D response to cholecalciferol supplementation( Reference Forsythe, Livingstone and Barnes 41 , Reference Barger-Lux, Heaney and Dowell 99 – Reference Waterhouse, Tran and Armstrong 106 ). In the majority of these studies, a significant inverse relationship was apparent between BMI and/or FM, and this occurred irrespective of population group and across a wide range of supplemental doses of cholecalciferol given for varying durations (1 week to 1 year)( Reference Forsythe, Livingstone and Barnes 41 , Reference Barger-Lux, Heaney and Dowell 99 , Reference Blum, Dallal and Dawson-Hughes 101 , Reference Lee, Greenfield and Seibel 103 – Reference Waterhouse, Tran and Armstrong 106 ). For example, in the study by Forsythe et al.( Reference Forsythe, Livingstone and Barnes 41 ), the mean adjusted change in 25(OH)D among older adults (≥64 years) decreased by approximately 6·5 nmol/l with every 5 kg/m2 increase in BMI at baseline. These data suggest that such individuals may require a larger dose of vitamin D or a longer supplemental period to achieve a desired vitamin D status, compared with their lean counterparts and independent of baseline concentrations. Similarly to the associations shown at baseline between vitamin D status, BMI and FM (Fig. 1), adiposity only attenuated the response to supplementation (15 μg cholecalciferol daily) in the older adults. The effect was NS in the younger adults (20–40 years)( Reference Forsythe, Livingstone and Barnes 41 ), which may suggest that the effect of adiposity on vitamin D status may become more prominent with increasing age. Moreover, another study has demonstrated that obese individuals are 2·3 times more likely to be deficient after prescribed ergocalciferol (vitamin D2) replacement( Reference Bryant, Koenigsfeld and Lehman 107 ). Therefore, the effect of adiposity on the 25(OH)D response to supplementation is not only specific to cholecalciferol.

Table 1. Studies investigating the effect of adiposity on the 25-hydroxyvitamin D response to cholecalciferol supplementation in adults

n, Number of subjects; yr, years; 25(OH)D, 25-hydroxyvitamin D; M, male; F, female; wk, week; NR, not reported; RCT, randomised controlled trial; mo, month; UVR, ultraviolet radiation.

* Study also included two additional treatment groups given either supplemental 25(OH)D3 (n 41) or 1,25-dihydroxyvitamin D3 (n 37).

† Study only reported mean (sd) age of the group.

‡ Defined as serum 25(OH)D < 50 nmol/l (20 ng/ml).

§ Dose administered monthly.

Overall, only two of the nine studies failed to replicate this finding. The first of these was relatively short in duration, uniquely opted for a weekly rather daily supplementation regime and did not appropriately adjust for seasonality in their analysis( Reference Canto-Costa, Kunii and Hauache 100 ). Similarly to the study by Forsythe et al.( Reference Forsythe, Livingstone and Barnes 41 ), the other showed no effect in younger premenopausal females( Reference Nelson, Blum and Hollis 102 ). It is also noteworthy that in the studies by Canto-Costa et al. ( Reference Canto-Costa, Kunii and Hauache 100 ) and Nelson et al. ( Reference Nelson, Blum and Hollis 102 ), the analysis was only carried out using FM, without considering simpler measures of body weight or BMI. This may suggest vitamin D is not being sequestered within the fat tissue, but that it is more likely volumetric dilution, and therefore body size (reflected by BMI) rather than FM per se that is influencing 25(OH)D concentrations in obesity.

Implications for setting dietary requirements

A recent meta-analysis by Zittermann et al.( Reference Zittermann, Ernst and Gummert 108 ) has concluded that body weight is an important predictor of the variation in 25(OH)D in cohorts taking supplements. From their analysis of ninety-four studies, including over 20 000 subjects and a wide range of supplemental doses, the authors calculated different daily required intakes of vitamin D based on age (30 v. 70 years), baseline and target 25(OH)D concentrations (from 25 up to 50 or 75 nmol/l), across different body weights (50–100 kg). These intake recommendations ranged from 5 μg to 84 μg daily depending on the combination of factors mentioned earlier( Reference Zittermann, Ernst and Gummert 108 ) and, similarly others have quantified this using other calculations and statistical approaches( Reference Hossein-nezhad and Holick 27 , Reference Holick, Binkley and Bischoff-Ferrari 109 , Reference Dhaliwal, Mikhail and Feuerman 110 ), with the common theme that ‘one size does not fit all’.

Although the evidence consistently supports a negative relationship between adiposity, vitamin D status and the 25(OH)D response to supplementation, it remains unclear if such evidence is relevant in the context of setting dietary requirements. Notwithstanding the fact that dietary requirements are derived to meet the needs of the majority of the general population, and not specific subgroups (e.g. the obese) over and earlier stage of the lifecycle, such recommendations must be cognisant of the increasing obesity prevalence among the general population. Indeed, in the Institute of Medicine's recent revision of the vitamin D dietary references intakes in the USA( 32 ), adiposity was recognised as a cofounder affecting 25(OH)D concentrations. The challenge of interpreting 25(OH)D concentrations in overweight and obese individuals was noted and the report also stated that the influence of body weight and body composition on 25(OH)D was a future research need to assist in the process of establishing requirements.

Conclusions

Overall, a large amount of evidence supports an inverse (albeit sometimes weak) association between adiposity and vitamin D status in adults, most likely attributable to volumetric dilution, and perhaps sequestration in adipose tissue to a lesser extent. Optimal vitamin D status or high vitamin D intakes also appear to be protective against future weight gain and/or diet-induced obesity, albeit the evidence for this in human subjects is not strong. On the other hand, little evidence currently supports a direct causal link between vitamin D and weight or FM loss and this merits further investigation. Future research should include well-designed, randomised controlled longer-term studies that robustly measure both body size (i.e. body weight or BMI) and body composition (i.e. FM). Notwithstanding the many practical challenges, such studies should also adequately control for time of year (seasonality), sun exposure and dietary intakes. Further mechanistic studies are also warranted to determine if vitamin D interacts with adipose tissue metabolism by anti-inflammatory or other mechanisms. Studies exploring the effects of adiposity on vitamin D status in groups ‘at-risk’ of vitamin D deficiency, such as pregnant women, other patient groups (e.g. chronic obstructive pulmonary disease patients), ethnic minorities and elite athletes are also needed.

Despite the somewhat formidable challenge of establishing a direct causal link between vitamin D and obesity, the evidence clearly shows that body weight and/or adiposity does negatively influence the 25(OH)D response to supplemental vitamin D. Although it remains to be elucidated if the same relationship is apparent in response to other dietary sources (e.g. fortified foods), such evidence does have implications for both setting dietary requirements and in the clinical setting to prevent and/or treat deficiency. Finally, recent insights from genetic analyses show promise for the use of personalised nutrition in the area of vitamin D and obesity, whereby certain VDR profiles may use to predict an individual's response to supplementation or indeed the risk of developing obesity in the future. Research is this area is particularly timely as the development of public health strategies to decrease the prevalence and/or impact of overweight and obesity are urgently required.

Acknowledgements

The author would like to acknowledge the Irish Section of the Nutrition Society for inviting this award lecture and Dr Maria Mulhern for providing comments on drafts of the review.

Financial Support

None.

Conflict of Interest

None.

Authorship

L. K. P. reviewed the literature and wrote the manuscript.

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Figure 0

Fig. 1. Association between mean (±1 se) serum 25-hydroxyvitamin D (25(OH)D) and (a) BMI categories, (b) tertiles of fat mass in apparently healthy adults aged 20–40 years (n 236) and ≥64 years (n 207). Based on data derived from Cashman et al.(39,40) and Forsythe et al.(41). BMI categories: healthy weight, BMI ≤ 24·9 kg/m2; Overweight, BMI 25·0–29·9 kg/m2; Obese, BMI ≥ 30·0 kg/m2. P-value denotes significance between groups from ANOVA. Bars with different letters are significantly different within that age-group (Tukey post hoc tests, P < 0·05).

Figure 1

Table 1. Studies investigating the effect of adiposity on the 25-hydroxyvitamin D response to cholecalciferol supplementation in adults