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The link between obesity and low circulating 25-hydroxyvitamin D concentrations: considerations and implications

Abstract

Obesity and vitamin D deficiency have both been recognized as major public health issues worldwide, and there is growing evidence that they are related, although the cause–effect relationship remains unclear. Could obesity be contributing to low circulating 25-hydroxyvitamin D concentrations? Alternatively, could low vitamin D status predispose to obesity? In this review, the relationship between low circulating 25-hydroxyvitamin D and obesity, and possible underlying reasons from both perspectives, is presented. One potential mechanism by which obesity could contribute to low serum 25-hydroxyvitamin D is adipose sequestration of vitamin D. On the other hand, adipose tissue has both the vitamin D receptor and the ability to synthesize 1,25-dihydroxyvitamin D, and there is evidence that vitamin D may regulate adipose tissue mass, differentiation and metabolism in ways that might contribute to obesity. Of particular interest, vitamin D deficiency is common both before and after bariatric surgery, and is often difficult to treat, particularly with the more malabsorptive procedures. Additional research is needed to elucidate the complex and multifaceted factors underlying the association between low circulating 25-hydroxyvitamin D and obesity, and to identify optimal treatment approaches in obese individuals and in bariatric surgical patients both before and after surgery.

Introduction

Obesity is well-recognized as a global epidemic1 and is associated with various co-morbidities, including hypertension, insulin resistance and other components of the metabolic syndrome.2, 3 Obesity and these related issues contribute significantly to modern healthcare costs, morbidity and mortality.4, 5 Furthermore, weight loss is difficult to achieve and sustain, and consequently many individuals, especially those who already have significant co-morbidities, are turning to bariatric weight loss surgery as a way to effectively treat obesity.6

Vitamin D deficiency has also been identified as a worldwide public health issue.7 The Institute of Medicine currently defines vitamin D deficiency as serum 25-hydroxyvitamin D concentration <20 ng dl−1 or <50 nmol l−1.8 Recent studies have opened up a new dimension regarding the relevance of vitamin D in health. Vitamin D has been suggested to be a potential factor in the prevention of many illnesses, including some cancers, autoimmune disorders, hypertension, diabetes2, 9, 10, 11, 12, 13, 14 and, even more speculatively, perhaps obesity itself.12 In this review, we will focus on the relationship between vitamin D deficiency and obesity in adults, including a discussion of potential underlying reasons for the strong association between these two modern health issues. We will also highlight bariatric weight loss as an example of a situation associated with high risk for vitamin D deficiency. Notably, bariatric patients are not only at increased risk before surgery, but they are often quite difficult to treat for vitamin D deficiency post-operatively, and we will discuss underlying contributors to this problem.

Materials and methods

A search of the literature using Ovid Medline was performed using the following search terms: (obesity OR bariatric surgery OR adipose) AND (vitamin D OR 25-OH vitamin D OR 25-hydroxyvitamin D OR 25-hydroxycholecalciferol OR calcidiol OR calcitriol OR 1,25-dihydroxyvitamin D OR 1,25-dihydroxycholecalciferol). This generated 719 articles, which were then limited to human, English language, adults over age 19 years and publication year 2006 to present, reducing the number to 207. Articles were then screened manually, and were excluded if any of the following criteria applied: review format, case study design, and failure to focus on vitamin D and obesity, weight loss, adipose tissue or bariatric surgery as a central theme of the paper. Seventy-six articles were identified and reviewed. Additional articles were included from the bibliographies of recently published review and research articles. With a few exceptions owing to uniqueness of research topic addressed or being recognized as ‘classic’ foundation knowledge, articles published before 2006 were excluded from this review.

Obesity and low circulating 25-hydroxyvitamin D are associated: what are the potential cause–effect relationships?

It has been well-observed that obese individuals frequently have below normal circulating 25-hydroxyvitamin D. There are two perspectives from which to view this relationship, and there is limited evidence to support both. First, the condition of obesity might be driving low serum 25-hydroxyvitamin D concentrations. On the other hand, it is possible that low circulating 25-hydroxyvitamin D itself may, at least in some circumstances, contribute to obesity or inhibit weight loss. We will begin with some general observations from both in vitro and human studies that suggest a link between obesity and low serum vitamin D concentrations. A thorough review of the relevant literature exploring the potential cause–effect relationships between these two important public health issues will follow.

In vitro studies show that the VDR and 1-α-hydroxylase enzyme are present in adipose tissue

It is now known that a number of non-renal tissues, including adipose, have both the nuclear vitamin D recepter (VDR) and the ability to synthesize 1,25-dihydroxyvitamin D through the 25-hydroxyvitamin D-1-α-hydroxylase enzyme, which can account for many of the emerging non-traditional roles of vitamin D throughout the body.15, 16 Kamei et al.17 were some of the first to observe that 3T3-L1 pre-adipocytes express the VDR. Querfeld et al.18 subsequently observed that matured 3T3-L1 adipocytes (by 10 days after differentiation) expressed receptors for vitamin D and parathyroid hormone (PTH). More recently, Li et al.19 showed the presence of the 1-α-hydroxylase enzyme in 3T3-L1 pre-adipocyte cells and in the adipose tissue of male Wistar rats. Therefore, adipose tissue, now appreciated as a metabolically active tissue, may both regulate and be regulated by vitamin D.

Obese subjects have altered vitamin D and PTH physiology

A number of investigators have observed that obese individuals tend to have low serum 25-hydroxyvitamin D, elevated PTH and variable 1,25-dihydroxyvitamin D concentrations. A detailed discussion of the relevant literature will follow. The observation that obesity is associated with below-normal serum 25-hydroxyvitamin D concentrations and/or overt deficiency is not new; however, as obesity prevalence has grown, so have the number of reports in the literature regarding this phenomenon.20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 Some of the most recent information about low vitamin D status and obesity comes from studies in bariatric surgery patients, reporting low preoperative circulating levels of 25-hydroxyvitamin D.21, 22, 23, 24, 25, 26, 27, 33, 34, 35, 36, 37, 38 In fact, a recent systematic review of 14 studies with about 1500 patients undergoing bariatric surgical procedures confirmed that obese individuals have serum 25-hydroxyvitamin D levels below 80 nmol l−1 preoperatively.39 Other investigators have reported that body mass index (BMI)25, 26, 40, 41, 42, 43, 44, 45, 46 and body fat20, 45, 47, 48, 49, 50, 51, 52 are inversely related to serum 25-hydroxyvitamin D. Although present in Caucasian populations as well, these observations have been reported to be even more prominent in African-Americans21, 26, 49, 50, 53 and Hispanic Americans.50 Winters et al.54 reported that African-American women (n=36) had lower serum 25-hydroxyvitamin D concentrations than White women (n=52); however, a negative association between BMI and serum 25-hydroxyvitamin D concentrations was only observed in the White women. By contrast, and in a particularly robust study sample (n=279), Carlin et al.21 reported that an inverse relationship between BMI and 25-hydroxyvitamin D was more common in extremely obese African-American individuals as compared with Caucasians scheduled for gastric bypass surgery.

Although various epidemiological studies and clinical trials show that obese individuals have low circulating levels of 25-hydroxyvitamin D, the relationship between obesity and the active form of the vitamin, 1,25-dihydroxyvitamin D, is less clear, in part because of the dynamic nature of the production and regulation of the active hormone. The normal physiological response to decreased serum 25-hydroxyvitamin D is an increase in serum PTH concentrations. Under conditions of low vitamin D status, serum 25-hydroxyvitamin D levels tend to be inversely associated with serum PTH concentrations, and PTH concentrations normalize when serum 25-hydroxyvitamin D levels increase to 30–40 ng ml−1 (75–100 nmol l−1).7 PTH stimulates the production of 1,25-dihydroxyvitamin D, which has a number of effects on bone metabolism,55, 56 as well as other effects related to its non-bone functions in the body.14 Several investigators have reported an inverse relationship between serum 25-hydroxyvitamin D and PTH in obese individuals.21, 33, 35, 36, 57, 58 Serum 1,25-dihydroxyvitamin D concentration may or may not be elevated, in part depending on the amount of 25-hydroxyvitamin D substrate that is available.55, 56 A substrate-dependent correlation between circulating 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D has been reported.59 Lagunova et al.59 observed that in overweight and obese individuals, serum 25-hydroxyvitamin D was the strongest predictor of serum 1,25-dihydroxyvitamin D, and that concentrations of both vitamin D metabolites varied by season. Other investigators have focused their attention on evaluating the active form of the vitamin in relation to other parameters. For example, Parikh et al.43 studied 302 healthy adults and found that low serum 1,25-dihydroxyvitamin D levels were associated with higher BMI and greater body fat measured by dual-energy X-ray absorptiometry in both Caucasian and African-American subjects, and, as has been reported by others,2, 60 that serum intact PTH was positively associated with BMI and adiposity. Similar results were obtained by Konradsen et al.,61 who studied the vitamin D endocrine system in over 2000 obese participants and reported a negative relationship between BMI and serum 1,25-dihydroxyvitamin D. Overall, the evidence strongly suggests that obese individuals have altered vitamin D and PTH physiology. In the next section, we will discuss how obesity itself could have a role in these alterations.

Could obesity contribute to low vitamin D status?

There are several potential mechanisms by which obesity could contribute to decreased serum 25-hydroxyvitamin D levels. Some investigators have suggested that sequestration of vitamin D by adipose tissue contributes to low circulating 25-hydroxyvitamin D concentrations in obese individuals.62, 63 There appears to be increased uptake and storage of vitamin D, which is fat-soluble, by the adipose tissue of obese individuals relative to that in lean individuals.62 Wortsman et al.62 exposed 38 subjects to UVB radiation and provided an oral dose of 50 000 IU of vitamin D2. The serum levels of vitamin D showed a relatively smaller increase in obese subjects as compared with that in non-obese subjects after either 24 h of UVB radiation or oral intake of vitamin D2. The levels of the vitamin precursor, 7-dehydrocholesterol, in the skin of the subjects did not differ. Blum et al.63 subsequently measured adipose tissue vitamin D3 concentrations in 17 obese subjects by liquid chromatography mass spectrometry and reported a strong inverse relationship between amount of fat tissue and serum vitamin D3 concentration, providing further evidence of fat tissue vitamin D storage in obese individuals. Studies of serum 25-hydroxyvitamin D changes after weight and fat mass loss provide additional perspective on this issue. For example, Lin et al.64 reported that individuals undergoing Roux-en-Y gastric bypass (RYGB) showed a transient increase in serum 25-hydroxyvitamin D at 1 month after surgery, although overall serum 25-hydroxyvitamin D concentrations decreased over the course of the 1-year follow-up period. They also reported a strong positive association between serum 25-hydroxyvitamin D and adipose mass, which is in contrast to findings of a negative association by other investigators. Lin et al. attributed their findings to the early release of vitamin D from adipose during the weight loss that occurred in preparation for and immediately following RYGB. Similar findings in post-RYGB patients were reported by Aasheim et al.,65 although they did not measure changes in fat mass. They reported an initial increase (at 6 weeks and 6 months after surgery) in serum 25-hydroxyvitamin D concentrations, which declined toward baseline by 1 year after RYGB. Tzotzas et al.66 reported that serum 25-hydroxyvitamin D concentrations increased with non-bariatric surgery-induced weight loss. Taken together, these studies provide some level of support for the notion that adipose tissue could be sequestering vitamin D, and that, at least during the early phases of weight loss, it is possible that vitamin D may be released into circulation. Additional work is needed to further elucidate this.

Various investigators have suggested additional potential reasons for obesity as a contributor to decreased circulating 25-hydroxyvitamin D. One hypothesis is that there may be increased catabolism of vitamin D with increasing adiposity owing to the local action of the 24-hydroxylase enzyme that has been found in human adipose tissue.19 Another hypothesis is that synthesis of 25-hydroxyvitamin D by the liver may occur at a lower rate in obese individuals relative to that in lean individuals. Obesity is associated with non-alcoholic fatty liver disease, and it has been observed that individuals with non-alcoholic fatty liver disease (n=60) had significantly reduced winter serum 25-hydroxyvitamin D concentrations as compared with that in healthy, weight-matched controls (n=60).67 Furthermore, serum 25-hydroxyvitamin D concentration was inversely associated with the degree of histological severity of hepatic steatosis, fibrosis and inflammation in the non-alcoholic fatty liver disease patients in this study,67 suggesting that, perhaps the deranged activity of the liver may lead to a reduction in the 25-hydroxylation of vitamin D, leading to a decrease in the serum 25-hydroxyvitamin D concentrations. It has also been proposed that obese individuals are less exposed to sunlight, leading to deficiency, potentially because of less involvement in outdoor activities and clothing habits resulting in less skin exposure.68 Indeed, a recent report found that obese individuals who exercise outdoors are 47% less likely to be vitamin D deficient than those who do not.69

Yet an additional question that has been posed is, whether total-body clearance of vitamin D could be increased during obesity-associated inflammation,39 and in vitro studies have shown that active vitamin D may have an anti-inflammatory effect.70 There are limited in vivo data relevant to this discussion in obese individuals. Visceral adiposity in particular is associated with inflammation,71, 72 and serum 25-hydroxyvitamin D has been observed to be inversely related to visceral adiposity in African-Americans.52 The proinflammatory state has been linked to risk for atherosclerosis, and several recent studies have investigated the potential role of vitamin D in outcomes related to cardiovascular disease. For example, a study of normal-weight, healthy Turkish men and women reported that vitamin D deficiency was associated with endothelial dysfunction and lipid peroxidation, and thus may be considered to be an independent risk factor for atherosclerosis; vitamin D repletion was associated with improvements in endothelial function.73 Oh et al.74 reported that vitamin D-deficient obese individuals (primarily African-American) with hypertension and type-2 diabetes showed reduced foam cell formation when their macrophages were incubated with 1,25-dihydroxyvitamin D3 and oxidized low-density lipoprotein (compared with macrophages incubated in vitamin D-deficient media); the effect appeared to be mediated by the vitamin D receptor. Under similar conditions, macrophages from obese control subjects with hypertension, but not type-2 diabetes, failed to show this reduction, suggesting that there may be a synergistic effect of diabetes and vitamin D deficiency on the propensity toward foam cell formation. By contrast, Freedman et al.52 reported that serum 25-hydroxyvitamin D concentrations were positively related to atherosclerotic plaque formation in African-Americans after adjusting for age, gender, BMI, glycosylated hemoglobin and glomerular filtration rate. Furthermore, there does not appear to be an association between serum 25-hydroxyvitamin D concentrations and inflammatory cytokines. Jorde et al.75 studied 324 obese individuals undergoing a 1-year cholecalciferol intervention (20 000 or 40 000 IU week−1) and found no clear relationship between serum 25-hydroxyvitamin D concentrations and circulating concentrations of inflammatory cytokines. Similarly, Vilarrasa et al.45 did not find a relationship between serum 25-hydroxyvitamin D concentrations and inflammatory cytokines in extremely obese individuals. Taken together, the data are inconclusive regarding the potential effect that obesity-associated inflammation may have on vitamin D status, and the role that low vitamin D status may have in inflammation in obese individuals. Clearly, further research is needed to more fully understand how obesity might be contributing to physiological alterations in the vitamin D system.

Could low vitamin D status contribute to obesity or inhibit weight loss?

Is there evidence that low serum 25-hydroxyvitamin D levels could predispose individuals to gain weight and/or fat mass, or inhibit weight or fat mass loss? In the sections below we will examine some of the preliminary findings from basic studies and the small number of human clinical research studies suggesting the possibility that vitamin D may regulate adipose tissue mass. However, there is much further work to be done in this particular area as currently the role of vitamin D in adipose regulation, both in magnitude and direction, is not clear.

Effects of vitamin D on genes related to adipocyte differentiation, lipolysis and lipogenesis. In vitro studies have evaluated the effects of 1,25-dihydroxyvitamin D3 and PTH on adipose tissue. Many of these studies used 1,25-dihydroxyvitamin D3 concentrations from 10−6 to 10−9M,18, 76, 77 and it is important to note that these are higher than the typical circulating concentration of 1,25-dihydroxyvitamin D3 in the human body (10−10M),78 although they could provide possible mechanisms by which vitamin D might have an anti-obesity effect. Some investigators within the past decade have examined the effects of vitamin D on gene expression and proteins related to adipose tissue differentiation and metabolism in cell culture experiments. Lipoprotein lipase (LPL), which has a role in adipocyte hypertrophy,79 is expressed during adipocyte differentiation and is a marker of adipocyte maturity.80 Similarly, the protein aP2 is a carrier of fatty acids, necessary for lipolysis, and is considered a late marker of adipocyte differentiation.81 Peroxisome proliferator-activated receptor-γ (PPAR gamma), CCAAT/enhancer-binding protein (C/EBP) and sterol-regulatory element-binding protein-1 (SREBP-1) are also involved in adipose tissue differentiation and act as transcriptional regulators to modulate gene expression and the functional proteins related to adipose function.82, 83, 84, 85, 86 Some investigators have found that 1,25-dihydroxyvitamin D3 appears to block adipose tissue differentiation by suppressing LPL, aP2, C/EBP-α, PPAR-γ and SREBP-1.76, 77 There is controversy, however. Querfeld et al.18 observed that 3T3-L1 adipocytes responded to calcitriol (in a dose-dependent manner) by significantly increasing the expression of LPL; however, these same cells, when treated with PTH, decreased the expression of LPL, suggesting that PTH and calcitriol have antagonistic effects on adipocyte LPL in vitro. In research related to vitamin D regulation of adiposity, gene expression of fatty acid synthase, an important enzyme involved in adipose tissue de novo lipogenesis, was found to be suppressed by 1,25-dihydroxyvitamin D3.77 These investigators77 also found that, when the VDR was overexpressed, pre-adipocyte differentiation was inhibited even in the absence of 1,25-dihydroxyvitamin D3, suggesting that the unliganded VDR could have an important role in adipogenesis inhibition.

While some of the aforementioned mechanisms would suggest potential anti-obesity actions of vitamin D, noteworthy studies performed in a recent animal model suggest that vitamin D could actually promote fat mass accumulation. Subsequent to their cell culture work discussed above, the group of Li87 found that, compared with wild-type littermates, VDR-knockout animals had very little adipose tissue mass and higher rates of adipose β-oxidation. More work is needed to follow up on these findings. It is of note that these studies involved a global knockout. Additional animal models, including adipose tissue-specific knockout models, and further translation into human studies, will better elucidate the function of the VDR in adipose tissue. There are limited human studies with in vitro data examining the role of vitamin D in adipose metabolism. One recent human study reported that vitamin D supplementation (2000 IU cholecalciferol per day for 7 days) with a low-calcium diet resulted in increased 1,25-dihydroxyvitamin D3 concentrations but had no apparent effect on energy expenditure or gene expression (mRNA) of the proteins and enzymes involved in lipogenesis or lipolysis, including uncoupling protein-2, fatty acid synthase, glycerol phosphate dehydrogenase-2, hormone-sensitive lipase or PPAR-γ when baseline subcutaneous adipose tissue biopsy levels were compared with those of samples obtained 7 days later.88 However, treatment duration and dose may not have been adequate to see significant effects on these parameters; gene expression may not mirror protein expression; and there could also potentially be depot-specific responses to local vitamin D concentrations.

In summary, basic studies are inconclusive in determining what, if any, significant role vitamin D might have in relation to adiposity. Additional properly designed experiments that accurately mirror human physiology should be conducted with vitamin D exposure at physiological concentrations in order to further elucidate this issue. Indeed, given that adipose tissue has 1-α-hydroxlase activity, it is possible that physiological tissue and intracellular concentrations of 1,25-hydroxyvitamin D levels may differ significantly from circulating levels, and that small differences in the level of this hormonal form of vitamin D may lead to significant alterations in local effects on adiposity. Additionally, further knockout models will also be important for enhancing our understanding of the role of vitamin D in fat mass regulation.

Effects of vitamin D status on weight loss success in human clinical research studies. Some investigators suggest that vitamin D has antiobesogenic effects because it has been observed that vitamin D status is associated with weight loss success. Specifically, there have been a small number of human clinical studies in which an association between baseline vitamin D status and subsequent weight loss success was identified. For example, Ljunghall et al.89 reported, as a secondary finding in a study designed to investigate the effect of vitamin D supplementation on insulin secretion, that subjects who received low-dose vitamin D (cholecalciferol) supplementation showed a small but significant loss of body weight as compared with subjects receiving placebo. Ortega et al.90 observed in a hypo-caloric weight loss intervention study that baseline serum 25-hydroxyvitamin D was a strong predictor of weight loss. In this study, women with higher baseline serum 25-hydroxyvitamin D concentrations experienced a greater degree of successful weight loss than women who had lower baseline serum vitamin D, despite having similar energy intakes. Teegarden et al.91 also conducted a hypo-caloric weight loss intervention trial, and they reported that in overweight and obese women on a 500-kcal day−1 deficit, baseline serum 25-hydroxyvitamin D concentration was a strong positive predictor of change in the thermic effect of a meal after 12 weeks of the diet: for example, the higher the baseline vitamin D concentration, the greater the thermic effect of food observed after meals. Although the mechanism is not clearly understood, it has been suggested that vitamin D may work synergistically with dietary calcium to increase postprandial fat oxidation,92 and that at least part of this effect could be because of the suppression of PTH by adequate vitamin D status.91 By contrast, two recent studies have not suggested a role for vitamin D in weight loss. Sneve et al.93 reported no effect of high-dose vitamin D supplementation on weight loss in their randomized, placebo-controlled trial of vitamin D supplementation in 400 overweight and obese individuals over 1 year. This study differed notably from some of the aforementioned studies in that it did not involve a hypo-caloric intervention. The only intervention tested by Sneve et al. was vitamin D administration alone. In another recent study, Zitterman et al.94 also did not find an effect of baseline vitamin D status on subsequent weight loss. These investigators did state that they were using a weight loss strategy; however, they did not provide sufficient details about the specific weight loss intervention to ascertain if a systematic hypo-caloric diet approach was taken, and they did not specify if an exercise intervention was included in the treatment protocol. Thus, it is possible that the effect that vitamin D has on adiposity may depend on other factors such as whether or not a hypo-caloric diet is being attempted, or what the vitamin D status is at the time of weight loss diet initiation, or perhaps some other factor closely related to vitamin D status such as PTH, as will be discussed below.

Could some other factor linked with low vitamin D status be a contributing causal factor in the low vitamin D status–obesity relationship?

Some investigators have suggested that it is not specifically low vitamin D status, but some other factor closely linked to low vitamin D status, such as elevated PTH, which promotes obesity and inhibits weight loss.95 It has been proposed that PTH inhibits lipolysis.18, 95 Others have proposed that low calcium status, which would be linked with low vitamin D status, is a contributor to the inability to lose weight, and thus high-calcium diets may help with weight loss by repleting calcium.96, 97 This hypothesis is controversial and studies of high-calcium diets have reported variable effects on weight loss. Holecki et al.98 reported that supplementation with calcium (2000 mg day−1) and cholecalciferol (1000 IU day−1) in individuals on a hypo-caloric weight loss regimen had no effect on weight or fat loss as compared with unsupplemented controls. By contrast, Shahar et al.99 reported recently that 6-month serum 25-hydroxyvitamin D concentrations and dairy calcium intake were associated with subsequent weight loss at 2 years in a study of 126 men and women on three different non-calorically restricted dietary regimens. Still others have hypothesized that low vitamin D status triggers a ‘winter’ response, a kind of hibernation state characterized by a lower metabolic rate.12

In summary, studies to date are inconclusive as to what effect vitamin D might have on adiposity, with some suggesting that weight/fat loss would be promoted, and others indicating that weight/fat loss would be inhibited and/or weight gain would be promoted by vitamin D. Clearly, the vitamin D–obesity relationship is not well understood yet, and there could be many factors influencing it, both directly and indirectly. Additional research is needed to elucidate the complex and multifaceted factors underlying the observed association between low vitamin D status and obesity.

Bariatric weight loss surgical patients: a special population with impaired vitamin D status

Bariatric surgery patients have been well-observed to have low circulating 25-hydroxyvitamin D concentrations.24, 25, 27, 33, 34, 36, 37, 38, 39, 58, 65, 100, 101, 102, 103 A number of factors have been proposed to be potential contributors to the low vitamin D status that is commonly seen in these patients. Many of these individuals have inadequate vitamin D levels prior to surgery,21, 22, 23, 24, 25, 26, 27, 33, 34, 35, 36, 37, 38 potentially owing to the obesity-related factors discussed above, which could contribute to low circulating 25-hydroxyvitamin D concentrations. A compromised vitamin D status may adversely affect clinical outcomes after surgery, although this issue has not been well-studied. A recent report by Carlin et al.104 suggested that low vitamin D status may prevent the postoperative amelioration of hypertension. In their study of 196 patients taking antihypertensive medication before gastric bypass, serum 25-hydroxyvitamin D concentrations below 20 ng ml−1 were associated with significantly lower rates of hypertension resolution (41 versus 61%, P<0.008). It remains to be seen what other potential effects the low pre-operative vitamin D status may have on clinical outcomes following bariatric surgery.

Bariatric surgery further complicates attempts to achieve adequate vitamin D status. The anatomic changes that occur with bariatric surgery can lead to challenges in optimizing postoperative vitamin D status. Vitamin D absorption is dependent on micellar solubilization within chylomicrons, with the most rapid absorption rate in the jejunum. However, given the longer transit time in the distal ileum, significant absorption also occurs there.105, 106 Vitamin D absorbed from the gastrointestinal tract enters circulation through the lymphatic circulation and the thoracic duct.106 Given the physiology involved with oral vitamin D absorption, malabsorptive procedures such as the biliopancreatic diversion make vitamin D repletion and maintenance even more challenging.37 Even the RYGB, which is not considered to be a purely malabsorptive procedure, but incorporates both restrictive and malabsorptive elements, presents challenges for vitamin D repletion, given that variable characteristics such as limb length can affect absorption.24

There are limited data on how best to treat low vitamin D status in bariatric surgery patients, and procedure-specific guidelines are unavailable. A few investigators have reported on the effects of routine vitamin D supplements using cholecalciferol doses found in standard multivitamins (200–400 IU day−1),65, 101 and this level of supplementation has typically been inadequate to restore serum 25-hydroxyvitamin D concentrations to normal. Other investigators have reported on the effect of supplementation with 800 IU vitamin D (and calcium) on vitamin D status in individuals after gastric bypass.33, 100 Flores et al.33 observed that in 71% of the patients, serum 25-hydroxyvitamin D concentrations remained below 75 nmol l−1 (30 ng ml−1) at 1 year after surgery. Carlin et al.100 reported similar findings, with half of the patients remaining vitamin D-deficient (serum 25-hydroxyvitamin D <50 nmol l−1 or 20 ng ml−1) at 1 year after surgery. In a particularly notable study, Aasheim et al.65 studied 60 bariatric surgery patients (31 RYGB, 29 duodenal switch) at multiple time points up to 1 year post-operatively and found that, although serum 25-hydroxyvitamin D concentrations increased after RYGB, they remained below normal for most patients even by 1 year after surgery. By contrast, duodenal switch patients showed a significant decrease in serum 25-hydroxyvitamin D after surgery, and had significantly lower postoperative serum 25-hydroxyvitamin D concentrations than RYGB patients, despite a comparatively greater dietary supplement use (89% of the duodenal switch patients took a vitamin D supplement as compared with 74% of the RYGB patients at 1 year after surgery). These results suggest that different bariatric procedures may require different supplementation strategies to maintain normal vitamin D status.

Few studies have evaluated the effects of higher doses of vitamin D on post-bariatric surgery vitamin D status.25, 26, 107 In a study designed to evaluate the optimal post-surgical vitamin D treatment dose, Goldner et al.35 randomized individuals after RYGB to three doses of cholecalciferol: 800, 2000 and 5000 IU per day. They found that all groups were vitamin D-inadequate (defined as serum 25-hydroxyvitamin D <30 ng ml−1 or 75 nmol l−1) at baseline, and that after 12 months, only 44, 78 and 70% of the individuals in the groups assigned to receive 800, 2000 and 5000 IU day−1 intake, respectively, were able to reach adequate vitamin D concentrations. Even with very high-dose supplementation, it can be challenging to achieve normal vitamin D concentrations in bariatric surgery patients. Stein et al.26 treated patients who had serum 25-hydroxyvitamin D concentrations below 62 nmol l−1 (25 ng ml−1) with either 50 000 IU ergocalciferol or 8000 IU cholecalciferol weekly for 8 weeks. On average, serum 25-hydroxyvitamin D concentrations increased from 38 to 59 nmol l−1 in the cholecalciferol group, and from 34 to 78 nmol l−1 in the ergocalciferol group, with >80% compliance reported across the two treatments. Individual responses were not reported, thus, it is unclear how many of the 27 individuals who were treated experienced normalization of serum 25-hydroxyvitamin D concentrations. In addition, the authors of this paper did not specify the type of bariatric surgery that the subjects underwent. In a more robust study, Mahlay et al.25 treated RYGB patients who had serum 25-hydroxyvitamin D concentrations below 32 ng ml−1 (80 nmol l−1) with 50 000 IU ergocalciferol weekly for 12 weeks, followed by 800 IU day−1. Thirty-two out of the 40 subjects who were followed at 6 months after surgery met the definition of low vitamin D status; 17 out of the 32 subjects responded to treatment (94% compliance), with serum 25-hydroxyvitamin D concentrations increasing to an average of 42 ng ml−1. The 15 subjects who did not respond to treatment also had good compliance to the high-dose regimen (86%), and it was unclear why they did not respond. Clearly, additional research is needed in order to establish evidence-based (and potentially procedure-specific) guidelines on optimal treatment of low vitamin D status following bariatric surgery.

The 2010 National Osteoporosis guidelines suggest the following for vitamin D-related optimization in this population: Monitoring of serum calcium, PTH and 25-hydroxyvitamin D every 3–4 months initially to achieve optimal levels (at least 30–50 ng ml−1 (75–125 nmol l−1) with normalized PTH), with monitoring every 6–12 months thereafter to make sure optimal levels are maintained.108 Further research is needed to more fully understand the physiological alterations to the PTH–vitamin D system seen in obese individuals before surgery; to more carefully define the impact of specific surgical factors on vitamin D status; and to optimize treatment approaches after surgery in this ever increasing clinical population.

Summary and conclusion

Various epidemiological studies and clinical trials show that obese individuals have low serum concentrations of 25-hydoxyvitamin D. This observed relationship between low vitamin D status and obesity may be because of mechanisms such as adipose sequestration. By contrast, low serum 25-hydroxyvitamin D could potentially contribute to obesity by effects on lipogenesis and/or adipogenesis that may occur in adipose tissue. In this review, we have summarized potential cause–effect relationships that may underlie this link. Additional studies are needed to understand the vitamin D physiology in adipose, and the relationship between obesity and low vitamin D status. Follow-up cell culture and animal model studies are needed, with ultimate translation into human studies. Clinical studies to determine optimal treatment guidelines are needed for surgical and non-surgical populations with obesity. Key questions that remain to be answered include the following:

  1. 1)

    Why is obesity associated with low vitamin D status?

  2. 2)

    What is the ‘optimal’ oral supplemental dose of vitamin D (taking into account all sources, including UVB exposure and dietary intake) in severely obese individuals, both before and after bariatric surgery?

  3. 3)

    Should patients with severe obesity and vitamin D deficiency be repleted for vitamin D before bariatric surgery, and what impact might that have on clinical outcomes?

In conclusion, in this review the relationship between low circulating 25-hydroxyvitamin D and obesity was discussed, including potential mechanisms through which each might impact the other. Regardless of the ultimate cause–effect balance in this relationship, treatment of low vitamin D status in individuals with obesity could have a large public health impact on a number of modern health issues, and thus, the questions posed here are both timely and important.

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Earthman, C., Beckman, L., Masodkar, K. et al. The link between obesity and low circulating 25-hydroxyvitamin D concentrations: considerations and implications. Int J Obes 36, 387–396 (2012). https://doi.org/10.1038/ijo.2011.119

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Keywords

  • vitamin D
  • deficiency
  • inadequacy
  • insufficiency
  • adipose

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