Review ArticleReductions in body weight and percent fat mass increase the vitamin D status of obese subjects: a systematic review and metaregression analysis☆,☆☆
Introduction
Vitamin D and parathyroid hormone are essential for calcium homeostasis and bone metabolism [1]. There is accumulating evidence that vitamin D plays an important role in extraskeletal health and diseases such as diabetes mellitus, cancers, cardiovascular disease, and autoimmune disorders [2], [3], [4], [5]. Serum 25-hydroxyvitamin D (25OHD) is the best clinical indicator of vitamin D status [1], and based on current cutoffs, the prevalence of vitamin D insufficiency worldwide is high. The escalating obesity crisis potentially contributes to this increasing incidence of vitamin D insufficiency because obese individuals have lower levels of 25OHD than their nonobese counterparts [6], [7], [8]. In fact, inverse associations among body weight, body mass index (BMI), and measures of body fatness with vitamin D status have been found across the lifespan [4], [7], [9], [10]. Differences in 25OHD levels can be attributed to age, race, geography, skin color, habitual clothing, and sun exposure among other factors [11]. However, as vitamin D is fat soluble, it is commonly considered that the lower levels in the obese could also be due to uptake by adipose tissue (AT) and its clearance from plasma.
Rosenstreich et al [12] were the first to propose that AT was the major storage site of vitamin D and that its release from this tissue was quite slow. Based on the available evidence from animals and man, Heaney et al [13] have confirmed that the distribution of 25OHD was highest in fat mass (FM) (34%), followed by serum (30%) and then muscle (20%). Worstman et al [14] instead referred to “sequestration” of 25OHD for their observation that ultraviolet B radiation resulted in a significant increase in serum vitamin D3 in nonobese compared to obese individuals. This implied that vitamin D “disappeared” into AT and other tissues and was not immediately available in plasma for further metabolic activity. Such a phenomenon would account for the lower bioavailability of the vitamin in the obese [14]; however, the mechanisms controlling the deposition and release of vitamin D from AT are still unknown [15].
Drincic et al [16], however, support the theory of volumetric dilution, which implies that plasma levels of the vitamin decrease as body size and hence fat stores increase. It follows that, if fat stores decrease, there ought to be a greater return of vitamin D into plasma resulting in increased vitamin D status. In a cross-sectional study, Drincic et al [16] identified body weight as the single strongest predictor of 25OHD levels, followed by FM. Their best fitting model relating 25OHD and body weight was a hyperbola, which indicated that body weight explained 13% of the variance in 25OHD. A visual inspection of the regression line shows that the slope is steeper at a body weight less than 90 kg but gets progressively shallower at higher body weights [16]. Hence, an obese individual of 100 kg would need to lose a considerable amount of weight to benefit from an appreciable increase in 25OHD. The results of a clinical trial would support this interpretation because categories of weight loss less than 15% of baseline brought about increases of 5.3 to 8.3 nmol/L in 25OHD, whereas above a value of 15%, there was more than a doubling of this effect [17]. A caveat to such expectations would be the extensive conversion of released vitamin D to metabolites other than 25OHD, which would not be detected by the specific 25OHD assay used (Fig. 1).
It is unclear how 25OHD is handled once taken up by different body tissues such as AT and skeletal muscle. Both tissues are metabolically active, and the vitamin D receptor (VDR) is expressed in them [18], [19]. Hence, a paracrine role in these tissues may account for some of the sequestration effect. Alternatively, if these tissues merely act as a store for the vitamin, then a sizeable amount would be available for release into plasma after tissue mobilization in response to weight loss [20]. There is also the possibility that both sequestration and volumetric dilution coexist in obese individuals. In Fig. 1, we schematically depict the basis of this review and the potential storage and release of 25OHD in an obese individual during weight loss. We focused on the larger stores of AT seen in overweight/obese individuals to allow for the best chance for hypothesized effects. We also negated the contribution from external sources of vitamin D by excluding study arms with vitamin D supplementation and those that reported excessive sunlight exposure during their trials. In this systematic review, we embarked on the hypothesis that weight loss without supplementary vitamin D would result in an increase in plasma 25OHD. We entertained the possibility that changes in 25OHD might be explained by volumetric dilution effect, sequestration effects, or other mechanisms (Fig. 1).
The aim of the search was to identify trials with weight loss that measured change in vitamin D status, but without vitamin D supplementation. Accordingly, placebo arms of trials that used vitamin D supplementation were included because we were only interested in relating the change in the 2 variables. Studies were identified through a systematic electronic search of Web of Science and PubMed Central databases over the period January 1994 to October 2015. One author (PP) conducted the search using the following terms: vitamin D, vitamin D-3, 25-hydroxy-vitamin D, 25-hydroxyvitamin D, serum 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D3, 25OHD, cholecalciferol, 25-OH vitamin D, 25-hydroxycholecalciferol, or serum 25OHD, and obese, overweight, caloric restriction, weight loss, fat mass, fat free mass, body mass index, BMI, or adipose tissue. Only articles published in the English language were included.
At the identification stage, the abstract was read, and the articles were selected, according to the following inclusion criteria: human clinical trials, weight loss study (through energy restriction, increased physical activity, or both), measurement of weight loss or body composition, study or placebo arm(s) without vitamin D supplementation, overweight/obese subjects, and change in serum 25OHD. Exclusion criteria included the use of the following terms in the abstract: vitamin D supplementation in all study arms, vitamin D–enriched foods greater than 800 IU/d, animal studies, gastric bypass/bariatric surgery studies, and duplicates of the same article retrieved from the 2 different databases. At the screening stage, the full text was read, and articles were screened based on the following inclusion criteria: change in serum 25OHD measured, included data for at least 1 index of weight change, and weight loss as the primary or secondary outcome. Articles were excluded if vitamin D supplements were used, diets included foods enriched with vitamin D to result in greater than 800 IU/d, or extreme exposure to sunlight was indicated. Additional studies were sourced by manually searching the reference list and included 2 published studies from our laboratory [21], [22]. After eligibility was determined, all randomized controlled trials (RCTs) were graded for their quality according to the Jadad score, with values greater than or equal to 3, indicating a high quality study [23], whereas 9 single-stranded studies were graded as zero. The overall process is outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA) [24] flow diagram (Fig. 2).
Data extraction was carried out by 1 investigator (PKP) on an excel spreadsheet developed by the statistician (YZ). Another investigator (MJS) cross-checked quality criteria assessment and data entry. Any discrepancies were reviewed and discussed. The change in mean and SD was calculated for body weight, FM, fat free mass (FFM), or BMI, for studies that provided only prevalues and postvalues. Where necessary, vitamin D intake data were converted to international units per day; and 25OHD status, to nanomoles per liter. Fat mass was extracted as percentages; and FFM, as kilograms, as most articles presented their data in this manner. All subjects were overweight or obese at baseline; thus, FM (percentages) is an appropriate measure during weight loss studies. Furthermore, it is common to use FM (percentages) and FFM (kilograms) to evaluate nutrition status [25].
Section snippets
Meta-analysis main effects
The primary outcome was the relationship of change in vitamin D status and change in weight/obesity status. The change in vitamin D status was calculated as postvalue minus the prevalue where a positive value implied an increase in the 25OHD status. Changes in the 4 main factors of interest in our article, (i) weight (kilograms), (ii) BMI (kilograms per square meter), (iii) FM (percentages), and (iv) FFM (kilograms), were also calculated as postvalue minus the prevalue; hence, a negative value
Systematic review
The search strategy generated 23 studies (14 RCTs and 9 single-stranded studies) whose key features are presented in Table 1. Of these studies, 12 were conducted in Europe [31], [32], [33], [35], [36], [37], [39], [41], [43], [46], [47], [48]; 5, in the United States [17], [34], [38], [40], [45]; 2, in Canada [44], [50]; 2, in Australia [21], [22]; and 2, in the Middle East [42], [49]. The study settings were all outpatient studies in a university setting or outpatient clinics. The 23 studies
Discussion
It is yet to be confirmed whether vitamin D is sequestered or undergoes a volumetric dilution in obesity. We questioned whether weight loss in the absence of vitamin D supplementation would increase circulating 25OHD. In this systematic review, 17 of 23 studies observed an increase in 25OHD with weight loss, but only 5 of these studies reported a significant correlation coefficient between the 2 variables [37], [46], [47], [48], [50]. Our metaregression analysis indicated a near significant
Acknowledgment
The authors sincerely thank Anne Gangloff, Andrea R Josse, Alice J Lucey, Trina A Ricci, Sue A Shapses, and Marta D Van Loan for graciously providing additional data from their trials. The authors acknowledge the useful feedback and insights of the reviewers that shaped this manuscript. PKP is the recipient of an Australian Postgraduate Award. MJS acknowledges the School of Public Health, Curtin University, for research support. There are no conflicts of interest to declare.
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Major finding: The data support a volumetric dilution of vitamin D in obesity but do not discount a sequestration effect.
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Model used: Systematic review of trials on human subjects.