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MED 240606

REVIEW

CURRENT
OPINION Vitamin D in obesity
Jennifer S. Walsh, Simon Bowles, and Amy L. Evans

Purpose of review
Vitamin D is essential for bone health, and may also have important functions in immunity and other
systems. Vitamin D deficiency is common, and testing and supplementation is increasing. Serum vitamin D
is lower in obese people; it is important to understand the mechanism of this effect and whether it indicates
clinically significant deficiency.
Recent findings
Vitamin D is fat soluble, and distributed into fat, muscle, liver, and serum. All of these compartments are
increased in volume in obesity, so the lower vitamin D likely reflects a volumetric dilution effect and whole
body stores of vitamin D may be adequate. Despite lower serum vitamin D, obese adults do not have
higher bone turnover or lower bone mineral density. Patients undergoing bariatric surgery do have bone
loss, and ensuring vitamin D sufficiency in these patients may help to attenuate bone loss.
Summary
Lower vitamin D in obese people is a consistent finding across age, ethnicity, and geography. This may not
always reflect a clinical problem. Obese people need higher loading doses of vitamin D to achieve the
same serum 25-hydroxyvitamin D as normal weight.
Keywords
bone, obesity, vitamin D

INTRODUCTION 1-hydroxylation in the kidney. The final step of

The main source of vitamin D in humans is produc- 1-hydroxylation is tightly regulated to prevent
tion from the action of ultraviolet-B (UVB) light on hypercalcaemia.
cholesterol in skin. There is a small contribution The main circulating form of vitamin D is
from dietary sources such as oily fish and fortified 25(OH)D. It is protein bound in circulation [about
foods. There are some geographical variations, for 85% to vitamin D-binding protein (VDBP), and
example, in Scandinavia, dietary fish is a major about 15% to albumin]. 25(OH)D is fat soluble,
source, and in the United States there is more food and distributed into fat, muscle, and liver, with
fortification. Vitamin D deficiency is very prevalent smaller amounts into other tissues. 25(OH)D is
in the northern hemisphere; most of the UK popu- cleared by 24-hydroxylation to 24,25(OH)2D or
lation are vitamin D deficient in winter [1]. other inactive metabolites.
There is ongoing debate about the fundamental Active vitamin D, 1,25(OH)2D is required for gut
principles of defining vitamin D deficiency. The absorption of dietary calcium. Severe vitamin D
most commonly used measure of vitamin D status deficiency causes osteomalacia in adults and rickets
is total 25-hydroxyvitamin D [25(OH)D] which cap- in children. Less severe insufficiency causes
tures 25(OH)D3 and 25(OH)D2. 25(OH)D has a long increased bone turnover and is associated with
serum half-life and is a technically easy measure- increased fracture risk. Vitamin D deficiency has
ment, but it has been proposed that free (nonprotein been associated with a wide range of other disorders,
bound) 25(OH)D is a better measurement because it particularly autoimmune disorders and cancers, but
more closely reflects biologically available 25(OH)D
status. There are variations in the sufficiency thresh- Mellanby Centre for Bone Research, University of Sheffield, Sheffield, UK
old recommended by different advisory bodies, Correspondence to Jennifer S. Walsh, MBChB FRCP PhD FHEA,
with recommendations generally between 50 and Metabolic Bone Centre, Northern General Hospital, University of Shef-
75 nmol/l [2,3]. field, Herries Road, Sheffield S5 7AU, UK. Tel: +44 144 2714705;.
Vitamin D is a prehormone. It is converted e-mail: [email protected]
to the active hormone 1,25 dihydroxyvitamin D Curr Opin Endocrinol Diabetes Obes 2017, 24:000–000
[1,25(OH)2D] by 25-hydroxylation in the liver and DOI:10.1097/MED.0000000000000371

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Parathyroids, bone, and mineral metabolism

tends to be higher in obesity [15], but the relation-

KEY POINTS ship between serum calcium and PTH is left-shifted
 Serum vitamin D is low in obese people across age, in obesity [16], so it is difficult to interpret the
ethnicity, and geography. clinical significance of higher PTH.
It is likely that low serum 25(OH)D is a conse-
 The low vitamin D is because of greater volumetric quence of obesity, rather than the cause of obesity. A
dilution, and may not necessarily indicate vitamin
large genetic study found that high BMI and genes
D deficiency.
that predispose to obesity decrease serum 25(OH)D,
 Despite lower serum vitamin D, obese people have whereas low 25(OH)D and genes associated with low
lower bone turnover and higher bone density than 25(OH)D have very little effect on obesity [17]. In
normal weight people. meta-analysis, vitamin D supplementation has no
&&

 Bariatric surgery does cause bone loss, and vitamin D effect on body weight or fat mass [18 ].
supplementation may be important in this group
of patients.
CAUSES OF LOW 25-HYDROXYVITAMIN D
 Obese people need higher loading doses of vitamin D IN OBESITY
than normal weight people to achieve a similar
increment in serum vitamin D. There are a number of possible mechanisms that
could cause low 25(OH)D in obesity. There could be
lower input because of lower dietary intake, lower
sunlight exposure, or impaired skin synthesis of
a causative role in these conditions is not yet well vitamin D. Alterations in protein binding or faster
established. metabolic clearance in obesity could lead to lower
Obesity is associated with low serum 25(OH)D. serum 25(OH)D. The lower serum 25(OH)D could be
This is a consistent finding in adults and children of because of distribution of 25(OH)D into a larger
different ethnicities in a range of geographic loca- whole body tissue volume, particularly if 25(OH)D
tions. This observation raises several questions: is was actively sequestered in other tissues.
the low serum 25(OH)D a consequence or cause of Dietary vitamin D intake did not differ between
obesity? What is the cause of low serum 25(OH)D in obese and normal weight adults in a UK population
&&
obesity? Does the low serum 25(OH)D in obesity [4 ]. Obese people may have less sunlight exposure
have clinical consequences for bone or other sys- than normal weight people [19] in some geographic
tems? Do obese people need higher doses of vitamin regions, although in two UK studies, sunlight expo-
D supplements? Does vitamin D supplementation in
&&
sure did not vary with BMI [4 ,20]. When exposed
obesity ameliorate any of the metabolic consequen- to UVB, normal weight and obese people have a
ces of obesity? What happens to vitamin D status similar cutaneous synthesis of vitamin D [21].
when weight changes rapidly after weight loss Clearly, diet and sunlight behaviours will vary
surgery? between different geographic and cultural groups,
and may be a contributory factor to lower vitamin D
in some groups.
RELATIONSHIP BETWEEN BODY WEIGHT Serum VDBP and albumin concentrations affect
AND VITAMIN D the total 25(OH)D measurement, and there are
Obese people have lower serum 25(OH)D than nor- genetic variations in VDBP which cause variation
mal weight people, and serum 25(OH)D is inversely in the binding affinity of VDBP. However, VDBP and
correlated with body weight, BMI, and fat mass. This albumin do not differ between obese and normal
has been shown in adults and children in northern weight people, and the distribution of VDBP geno-
and southern Europe, Australia and New Zealand, types is similar in obese and normal weight groups
&&
Saudi Arabia, Latin America, and in White, Black, [4 ,22].
&&
and Hispanic groups in the United States [4 ,5–12]. If metabolic clearance rate of 25(OH)D were
Serum 25(OH)D is about 20% lower in obese people faster in obesity, the half-life of 25(OH)D would
&&
than normal weight [4 ,5,13], and the prevalence be shorter and circulating 25(OH)D would be lower.
of 25(OH)D deficiency is greater in obese people, Measurements using a stable isotope 25(OH)D tracer
&&
reported at between 40 and 80% [4 ,9,12]. show that metabolic clearance is similar in obese
&&
Other measures of vitamin D status [free and normal weight adults [4 ], so this is unlikely to
25(OH)D and 1,25(OH)2D] are also lower in obesity be the explanation for lower serum 25(OH)D.
&&
[4 ,14]. The most important mechanism is probably
Parathyroid hormone is often used as an indica- volumetric dilution of 25(OH)D into greater tissue
tor of vitamin D status. Parathyroid hormone (PTH) volume in obese people. 25(OH)D is distributed into

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Vitamin D in obesity Walsh et al.

the dose–response does not seem consistent with

that hypothesis. There is experimental evidence that
vitamin D concentration in abdominal subcutane-
ous fat increases with vitamin D supplementation
[28,29], and one in-vitro study suggests that adipo-
cytes from insulin-resistant obese people might
have impaired release of vitamin D [30]. Adipocytes
express 1-hydroxylase which activates 25(OH)D, but
also 24-hydroxylase, which inactivates 25(OH)D.
The activity of the enzymes may be altered in obe-
sity, which could affect the amount of 25(OH)D
available for release into serum [31]. However, the
distribution and concentration of vitamin D and
25(OH)D in subcutaneous and omental fat does
not differ between obese and normal weight people,
FIGURE 1. Serum response to oral vitamin D supplementation and the correlation between 25(OH)D in subcuta-
is BMI and dose dependent. The time course of the 25(OH)D neous fat and serum is similar in obese and normal
increment in the obese 1000-IU group (*), the obese 5000- weight [32].
IU group (^), and the obese 10 000-IU group (&) in the
current study, contrasted with a historical comparison from
normal-weight men who were taking 5000 IU (^) and DOES LOWER 25-HYDROXYVITAMIN D
10 000 IU (&) daily. The error bars are 1 SEM. Reproduced HAVE CLINICAL CONSEQUENCES IN
with permission [27]. SEM, standard error of the mean. OBESITY?
Usually, low total 25(OH)D, free 25(OH)D, and
1,25(OH)2D would lead to lower dietary calcium
serum, fat, muscle, liver, and a small amount into absorption, and increased bone turnover with lower
other tissues [23], and all of these compartments are bone mineral density (BMD). However, obese adults
increased in obesity. The difference in serum have lower bone turnover than normal weight,
25(OH)D between obese and normal weight groups and higher BMD with thicker, denser cortices and
is greater in summer than in winter because the greater trabecular number [33]. It is important to
summer rise in serum 25(OH)D is less in obese note that in contrast, obesity in children has adverse
&&
people [4 ,24,25]. Obese people get similar sunlight effects on bone strength [34].
exposure as normal weight people, and produce the The lack of adverse effects on bone may indicate
same amount of vitamin D in response to sunlight that obese people are not truly vitamin D deficient;
exposure, but the synthesized vitamin is distributed it is possible that although serum 25(OH)D is lower
into a larger volume, so the amount distributed into because of volumetric dilution, their whole body
serum is less. There is a similar difference between vitamin D stores are greater because of the reservoir
obese and normal weight people in response to oral in their fat tissue, which maintains an equilibrium
vitamin D dosing, with a smaller serum 25(OH)D with serum 25(OH)D and a sufficient supply.
rise in obesity [26]. The dose–response relationship An alternative explanation is that obese people
of vitamin D supplementation in obese adults is BMI are vitamin D deficient but that other effects of
dependent and curvilinear, consistent with volu- obesity compensate for the effects of vitamin D
metric dilution [27] (Fig. 1). The clinical implication deficiency. For example, greater skeletal loading
of this volumetric dilution effect is that obese people or the action of hormones such as leptin, adiponec-
will need larger loading doses of vitamin D than tin, or oestrogen are known to have positive effects
normal weight people to achieve the same serum on bone mass.
level of vitamin D, but on cessation of supplemen- If obese people are truly vitamin D deficient,
tation may have a slower decrease in serum vitamin there may be implications for systems other than
D because of redistribution from other tissue stores. bone. Vitamin D deficiency has been associated with
Conversely, people with low body weight would a large number of disorders, such as autoimmunity,
have a large rise in serum vitamin D after dosing cancer, neurodegenerative disease, and metabolic
(because of the smaller volume of distribution), but syndrome. However, there is not yet clear evidence
would become deficient again quickly if supplemen- for a causative role of vitamin D deficiency in many
tation was stopped (because of less tissue storage). of these conditions [35]. Obesity does increase the
It has been proposed that vitamin D is actively risk for several of these disorders but there are other
retained (sequestered) in fat but the modelling of possible mechanisms than low vitamin D for these

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Parathyroids, bone, and mineral metabolism

associations, and the interaction of vitamin D and subsequent change in serum 25(OH)D [44]. With
obesity in causation has not yet been clearly char- biliopancreatic diversion, serum 25(OH)D tends to
acterized [36]. decline immediately after surgery, which is probably
In the US National Health and Nutrition Exami- because of the greater bile and fat malabsorption
nation Survey population study, low serum 25(OH)D with this procedure [45].
was associated with higher all-cause mortality in In the longer term, vitamin D decreases. Five
postmenopausal women with normal waist circum- years after RYGB, with calcium and vitamin D sup-
ference; the hazard ratio for the lowest versus the plementation in most patients, they are just vitamin
highest serum vitamin D quartile (<36.5 versus D sufficient at about 50 nmol/l, but have parathyroid
>65.4 nmol/l) was 1.85 (95% confidence interval hormone above the reference range [46]. Bone den-
1.00–3.44). In women with abdominal obesity there sity and microarchitecture deteriorated for at least
was no association between serum 25(OH)D quartile 2 years after RYGB, beyond stabilization of body
and all-cause mortality (hazard ratio 0.96, 95% con- weight, despite vitamin D supplementation which
fidence interval 0.52–1.76) [37]. This result suggests maintained serum 25(OH)D well into the replete
&&
that obesity does modulate the relationship between range [47 ]. The bone loss is likely to be multifacto-
serum vitamin D and health outcomes. rial, with decreased loading, changes in adipokines,
gut hormones, insulin, and sex hormones as well as
other nutritional factors. Maintaining vitamin D suf-
DOES VITAMIN D SUPPLEMENTATION ficiency after bariatric surgery may require higher
IMPROVE THE ADVERSE METABOLIC doses than standard supplementation, but in combi-
PROFILE IN OBESITY? nation with calcium and protein supplements and
A recent meta-analysis found only four or five good physical activity may attenuate bone loss [48].
quality intervention studies for each of the meta-
bolic parameters they considered (fat mass, blood
pressure, lipids, and glucose tolerance). There were OPTIMUM VITAMIN D DOSING FOR BMI
some positive effects of vitamin D supplementation As explained above, the observed serum 25(OH)D of
on fat mass, triglycerides, high density lipoprotein about 20% below the normal weight population in
cholesterol, and oral glucose tolerance, but adverse obese people may not indicate true deficiency or
effects on low-density lipoprotein cholesterol and a clinical problem. However, despite higher total
blood pressure. However, because of the small num- body stores, obese people can become vitamin D
bers of studies and significant heterogeneity of deficient for the same reasons as any other group. If
methodology, the current evidence is insufficient obese people are treated to the same serum 25(OH)D
to draw conclusions [38]. repletion threshold as normal weight, higher loading
Inflammatory markers do not seem to be higher doses will be required because of the greater volume
in vitamin D deficient obese people than in vitamin of distribution. Obese people may need repeated
D replete obese people [39] and vitamin D supple- loading courses to achieve repletion. (Conversely,
mentation has little effect on circulating inflamma- people with below-normal BMI may need lower
tory markers in overweight or obese people [40–42]. doses, but more frequently). Drincic et al. [27]
describes the formula to calculate the required
vitamin D dose based on BMI and the required incre-
VITAMIN D WITH WEIGHT LOSS SURGERY ment in serum 25(OH)D. Because there are no alter-
Obesity surgery leads to substantial weight loss in ations in protein binding or metabolic clearance rate
most patients, often about 30% of their body in obesity, maintenance dose requirements should be
weight. The two main types of surgery are gastric similar to normal weight (although as above, higher
volume reduction (e.g. sleeve gastrectomy) or doses may be need after bariatric surgery).
malabsorptive [most commonly Roux-en-Y gastric
bypass (RYGB), and less commonly biliopancreatic
diversion with gastric switch]. As expected, obese SUMMARY
people have low serum 25(OH)D preoperatively. Obesity is associated with lower serum vitamin D,
Most studies find that serum 25(OH)D increases in assessed as total 25(OH)D, free 25(OH)D, or
the first month after surgery [43], which may reflect 1,25(OH)2D. This is likely because of volumetric
the smaller volume of dilution with weight loss. One dilution into the greater volumes of serum, fat,
study tried to determine whether the vitamin D muscle, and liver. The observed lower serum vita-
stored in fat was mobilized into serum during weight min D in obesity does not seem to have adverse
loss, but found no association between vitamin D consequences for bone health. There is less available
concentration in fat at time of surgery and information about consequences for other systems,

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Vitamin D in obesity Walsh et al.

5. Macdonald HM, Mavroeidi A, Barr RJ, et al. Vitamin D status in postmeno-

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assay kits from Biomedica, consulting fees from Shire Meta-analysis included 26 randomized clinical trials with a total of 42 430 parti-
cipants (median duration, 12 months). Vitamin D supplementation compared with
and Mereo Biopharma. S.B.: donation of drug from placebo, or calcium and vitamin D compared with calcium alone had no significant
Consilient for clinical study. effect on BMI, weight, or fat mass.
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