ABSTRACTBackground Obesity is associated with vitamin D ins.docx

ABSTRACT
Background: Obesity is associated with vitamin D insufficiency
and secondary hyperparathyroidism.
Objective: This study assessed whether obesity alters the cuta-
neous production of vitamin D3 (cholecalciferol) or the
intestinal
absorption of vitamin D2 (ergocalciferol).
Design: Healthy, white, obese [body mass index (BMI; in
kg/m2)
≥ 30] and matched lean control subjects (BMI ≤ 25) received
either whole-body ultraviolet radiation or a pharmacologic dose
of vitamin D2 orally.
Results: Obese subjects had significantly lower basal 25-
hydroxyvitamin D concentrations and higher parathyroid hor-
mone concentrations than did age-matched control subjects.
Evaluation of blood vitamin D3 concentrations 24 h after
whole-body irradiation showed that the incremental increase
in vitamin D3 was 57% lower in obese than in nonobese sub-
jects. The content of the vitamin D3 precursor 7-dehydrocho-
lesterol in the skin of obese and nonobese subjects did not dif-
fer significantly between groups nor did its conversion to
previtamin D3 after irradiation in vitro. The obese and
nonobese subjects received an oral dose of 50 000 IU (1.25
mg) vitamin D2. BMI was inversely correlated with serum
vitamin D3 concentrations after irradiation (r = �0.55,
P = 0.003) and with peak serum vitamin D2 concentrations
after vitamin D2 intake (r = �0.56, P = 0.007).
Conclusions: Obesity-associated vitamin D insufficiency is
likely due to the decreased bioavailability of vitamin D3 from
cutaneous and dietary sources because of its deposition in body
fat compartments. Am J Clin Nutr 2000;72:690–3.

KEY WORDS Vitamin D, ultraviolet radiation, tanning bed,
obesity, 25-hydroxyvitamin D, parathyroid hormone, obesity,
vitamin D3, sunlight, obesity, 25-hydroxyvitamin D3,
bioavailability
INTRODUCTION
Obese individuals, as a group, have low plasma concentra-
tions of 25-hydroxyvitamin D [25(OH)D] (1–5), which are asso-
ciated with increased plasma concentrations of immunoreactive
parathyroid hormone (1, 6, 7). Although the explanation for the
increased risk of vitamin D deficiency in obesity is unknown, it
has been postulated that obese individuals may avoid exposure
to
solar ultraviolet (UV) radiation, which is indispensable for the
cutaneous synthesis of vitamin D3 (3). Alternatively, it has been
proposed that production of the active vitamin D metabolite
1,25-dihydroxyvitamin D [1,25(OH)2D] is enhanced and thus,
its
higher concentrations exert negative feedback control on the
hepatic synthesis of 25(OH)D (1). It has also been suggested
that
the metabolic clearance of vitamin D may increase in obesity,
possibly with enhanced uptake by adipose tissue (2).
Clarification of the mechanism for the subnormal concentra-
tions of 25(OH)D in obesity is nevertheless relevant for the
man-
agement of this highly prevalent condition. If, for example, the
increased risk of vitamin D deficiency were the expression of a
lack of exposure to sunlight, it would perhaps be only of acade-
mic interest. Conversely, if the increased risk of vitamin D defi-
ciency in obesity were the result of a primary alteration or a
direct
consequence of obesity itself then a rational intervention could

be
instituted. We therefore performed dynamic testing to evaluate
the blood concentrations of vitamin D in obese and nonobese
sub-
jects in response to UV-B irradiation or an oral dose of vitamin
D2.
We also performed studies in vitro to determine whether obesity
affects the cutaneous production of vitamin D3.
SUBJECTS AND METHODS
Subjects
The experimental population was 19 healthy whites (skin
types II and III) of normal body weight [body mass index (BMI;
in kg/m2) ≤ 25] and 19 healthy, obese subjects (skin types II
and III; BMI > 30). Subjects were recruited among medical
school personnel and had similar socioeconomic status. None of
the subjects had a history of hepatic or renal disorders and none
were taking vitamin D supplements, anticonvulsant medica-
tions, or corticosteroids. The study was performed during the
winter (November through February) and the subjects refrained
from sunlight exposure beginning 24 h before the study and dur-
ing the study. All subjects gave their informed consent and the
study was approved by the Jefferson Medical College (Philadel-
phia) Institutional Review Board.
Am J Clin Nutr 2000;72:690–3. Printed in USA. © 2000
American Society for Clinical Nutrition
Decreased bioavailability of vitamin D in obesity1–3
Jacobo Wortsman, Lois Y Matsuoka, Tai C Chen, Zhiren Lu,
and Michael F Holick
690

1 From the Southern Illinois University School of Medicine,
Springfield;
Jefferson Medical College, Philadelphia; and the Boston
University Med-
ical Center.
2 Supported by grant nos. MO1RR 00533 and AR 369637 from
the
National Institutes of Health.
3 Reprints not available. Address correspondence to MF Holick,
Boston
University School of Medicine, 715 Albany Street, M1013,
Boston, MA
02118. E-mail: [email protected]
Received August 31, 1999.
Accepted for publication January 19, 2000.
Original Research Communications
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Methods
The study of cutaneous vitamin D3 synthesis in response to
UV-B irradiation consisted of submitting the subjects to whole-
body irradiation in a phototherapy unit that emits wavelengths
of
260–330 nm as described previously (8). The radiation
delivered

at these wavelengths was 0.2 mW/cm2, determined at a distance
of 30 cm from the source. A single, 27-mJ/cm2 suberythemic
dose
of UV-B (290–320 nm) was delivered (one minimal erythema
dose: 33–36 mJ/cm2). Because peak serum vitamin D3
concentra-
tions occur 24 h after acute UV-B radiation exposure (9), blood
samples were obtained 1 h before (basal determination) and 24 h
after UV-B radiation exposure. Changes in serum vitamin D3
con-
centrations over this period reflected the synthesis and transport
of vitamin D3 from the skin into the bloodstream (10).
The study of the response to an oral challenge with vitamin D2
was performed ≥ 1 mo after the study of cutaneous vitamin D3
photosynthesis. The oral vitamin D2 loading test consisted of a
modification of the vitamin D absorption test described previ-
ously by Lo et al (11). Subjects were instructed to avoid dairy
products for 1 wk before the study and to fast from 2000 the
night before the test. A basal blood sample was obtained at
0800,
and immediately thereafter the subjects ingested a capsule of
vita-
min D2 [50 000 IU (1.25 mg) ergocalciferol] with 120 mL
water.
Subjects were allowed to eat 1 h later. Follow-up blood samples
were obtained 6, 10, and 24 h after the intake of vitamin D2.
Serum
was separated promptly and stored at �20 �C until analyzed.
The serum assays for vitamin D2 and vitamin D3 were per-
formed by HPLC (12). The intraassay and interassay variations
for this assay were 10% and 13%, respectively. The serum
assays
for 25(OH)D and 1,25(OH)2D were performed by using
binding-

protein assays as described previously (13, 14). The intraassay
and interassay variations for the 25(OH)D and 1,25(OH)2D
assays were 8% and 10% and 10% and 12%, respectively.
Parathyroid hormone concentrations (midmolecule assay; Star
Corp Inc, Stillwater, MN) were measured at the Medical
Univer-
sity of South Carolina, Charleston.
A total of 13 control (age: 34 ± 3 y; BMI: 22.2 ± 0.04) and
13 obese (age: 37 ± 2 y; BMI: 38 ± 1.7) individuals participated
in the study of the cutaneous synthesis of vitamin D3 in
response
to UV-B irradiation and 11 control (age: 36 ± 4 y; BMI:
21.4 ± 0.6) and 11 obese (age: 39 ± 3 y; BMI: 35.7 ± 1.8) sub-
jects participated in the oral vitamin D2 loading test. There was
some overlap among the experimental subjects; 5 nonobese and
7 obese subjects participated in both studies. Nevertheless,
char-
acteristics of the population included in each study were
similar.
In vitro studies
The direct effect of obesity on the synthetic capacity of the
skin to produce vitamin D3 was studied in whole skin
(epidermis
and dermis) obtained during surgery from 2 obese subjects (age:
27 and 84 y) and 2 nonobese subjects (age: 42 and 73 y) with
skin type III. The skin specimens were frozen and stored at
�70 �C promptly after removal. Before analysis, the skin sam-
ples were thawed at room temperature and the epidermis, where
most of the synthesis of vitamin D3 takes place, was separated
from the dermis (15). Individual skin pieces (1 cm2) were
exposed to simulated sunlight for the same period of time, after
which the epidermis was immediately removed and analyzed for

its combined vitamin D3 content (the combination of previtamin
D3
and vitamin D3) as described previously (15). The vitamin D3
precursor 7-dehydrocholesterol and its photoproduct previta-
min D3 were measured in triplicate by HPLC (15).
Statistical analysis
Individual comparisons between the 2 groups were per-
formed with Student’s t test. Changes across the 4 time points
were compared between the 2 groups in the oral study by using
a two-factor repeated-measures analysis of variance. Linear
relations between BMI and different variables were computed
by using Pearson correlation coefficients (16). Results were
considered significant if P values were < 0.05. All results are
expressed as means ± SEMs.
RESULTS
In the UV-B irradiation study, basal concentrations of vita-
min D3 were not significantly different between the obese and
nonobese control groups (Figure 1). There was a significant
increase in the circulating concentrations of vitamin D3 in both
groups 24 h after irradiation. There was also a significant
differ-
ence (P = 0.0042) between the response of each group, with the
VITAMIN D AND OBESITY 691
FIGURE 1. Mean (± SEM) serum vitamin D3 (cholecalciferol)
concentrations before (�) and 24 h after (�) whole-body
irradiation
(27 mJ/cm2) with ultraviolet B radiation. The response of the
obese sub-
jects was attenuated when compared with that of the control
group.

There was a significant time-by-group interaction, P = 0.003.
*Signifi-
cantly different from before values (P < 0.05).
FIGURE 2. Mean (± SEM) serum vitamin D2 (ergocalciferol)
con-
centrations in the control (�) and obese (�) groups 0–25 h after
oral
intake of vitamin D2 (50 000 IU, 1.25 mg). Vitamin D2 rose
rapidly until
�10 h after intake and then declined slightly thereafter.
*Significant time
and group effects by ANOVA (P < 0.05) but no significant time-
by-
group interaction. The difference in peak concentrations
between the
obese and nonobese control subjects was not significant.
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obese subjects showing an attenuated response to UV-B irradia-
tion. When the results were recalculated as the difference
between
basal and postirradiation vitamin D3 concentrations, they were
still significantly different [control subjects: 38.3 ± 5.5 nmol/L
(15.3 ± 2.1 ng/mL); obese subjects: 17.4 ± 3.6 nmol/L
(6.7 ± 1.4 ng/mL); P = 0.0029].
In the oral vitamin D2 loading test, basal serum concentrations
of vitamin D2 were not significantly different between groups
[control subjects: 5.3 ± 0.2 nmol/L (2.1 ± 0.6 ng/mL); obese

sub-
jects: 3.5 ± 1.5 nmol/L (1.4 ± 0.6 ng/mL); Figure 2].
Additionally,
there were no significant differences in basal vitamin D3
concen-
trations [control subjects: 2.5 + 1.8 nmol/L (1.0 ± 0.7 ng/mL);
obese subjects: 2.3 ± 2.3 nmol/L (0.9 ± 0.9 ng/mL)] or
1,25(OH)2D
[control subjects: 104.6 ± 14.6 pmol/L (43.5 ± 5.8 pg/mL);
obese subjects: 96.6 ± 6.7 pmol/L (40.2 ± 2.8 pg/mL)]. How-
ever, 25(OH)D concentrations were significantly lower
[50.0 ± 7.5 nmol/L (20.0 ± 3.4 ng/mL) compared with
84.8 ± 10.3 nmol/L (33.9 ± 4.1 ng/mL); P = 0.017] and para-
thyroid hormone concentrations were significantly higher
(0.80 ± 0.05 compared with 0.63 ± 0.04 pmol/L; P = 0.0291) in
the obese subjects than in the control subjects. After the oral
intake of vitamin D2, there was a marked increase in serum
vita-
min D2 concentrations, with a significant effect of both time
(P = 0.00001) and group (P = 0.0186); there was no significant
time-by-group interaction (Figure 2). Peak vitamin D2
concentra-
tions did not differ significantly between the 2 groups [control
sub-
jects: 233.3 nmol/L (92.4 ng/mL); obese subjects: 181.6 nmol/L
(71.9 ng/mL); P = 0.0603] nor did the difference between peak
and
basal vitamin D2 concentrations [control subjects: 230.6 nmol/L
(91.3 ng/mL); obese subjects: 185.4 nmol/L (73.4 ng/mL)].
There was a significant difference in the kinetics of the
25(OH)D
response between groups (P = 0.0481, ANOVA time-by-group
interaction; Figure 3). Follow-up analysis showed that the effect
of time was significant (P = 0.0041), whereas the effect of
group
was not. Testing for changes in vitamin D2 and 1,25(OH)2D

con-
centrations throughout the oral vitamin D2 loading test showed
that the group-by-time interaction, the time effect, and the
group
effect were not significant.
The effect of BMI on blood concentrations of vitamin D and its
metabolites were evaluated by determining the correlation
coeffi-
cients for the relations. Correlations between BMI and basal
vita-
min D2, basal 25(OH)D, 25(OH)D, basal 1,25(OH)2D, peak
25(OH)D, and basal vitamin D were not significant. Conversely,
there were 2 correlations that were highly significant: those
between BMI and peak serum vitamin D2 concentrations after
the
oral vitamin D2 load (Figure 4) and between BMI and serum
vitamin D3 concentrations after UV-B irradiation (Figure 5).
The percentage conversion of provitamin D3 (7-dehydrocholes-
terol) to vitamin D3 in skin was not significantly different
between
the young obese and young nonobese subjects (9.4 ± 1.9% com-
pared with 9.6 ± 1.1%) nor between the older obese and older
nonobese subjects (7.6 ± 0.5% compared with 7.3 ± 0.5%).
DISCUSSION
The present study of the synthesis and processing of vitamin D
confirmed that obese patients have lower basal 25(OH)D and
higher serum parathyroid hormone concentrations than do
nonobese
persons (1–5). To determine why obese individuals are prone to
vitamin D deficiency, we conducted a series of studies to deter-
mine their capability to handle vitamin D originating from

either
the oral route or from the skin. Because vitamin D is fat soluble
and is readily stored in adipose tissue, it could be sequestered in
the larger body pool of fat of obese individuals. We observed
that
blood vitamin D3 concentrations increased in both the obese
and
nonobese subjects after exposure to an identical amount of UV-
B
irradiation. Moreover, the obese subjects had a larger body
surface
area of exposure and therefore would be expected to produce
more
vitamin D3, resulting in higher blood vitamin D3
concentrations,
than would the nonobese control subjects. However, the
increase
in blood vitamin D3 concentrations was 57% less in the obese
than
in the nonobese subjects 24 h after the exposure. The content of
the vitamin D3 precursor 7-dehydrocholesterol in the skin was
not
significantly different between obese and nonobese subjects,
con-
sistent with previous observations (17, 18). Furthermore, the
per-
centage conversion to previtamin D3 and vitamin D3 was
similar in
both groups. Thus, obesity did not affect the capacity of the
skin
to produce vitamin D3, but may have altered the release of
vitamin
D3 from the skin into the circulation.
It is possible that the subcutaneous fat, which is known to
store vitamin D3, sequestered more of the cutaneous

synthesized
vitamin D3 in the obese than in the nonobese subjects because
there was more fat available for this process. To determine
whether the same phenomenon occurred when vitamin D was
692 WORTSMAN ET AL
FIGURE 3. Mean (± SEM) serum 25-hydroxyvitamin D
[25(OH)D]
concentrations in the control (�) and obese (�) groups 0–24 h
after oral
intake of vitamin D2 (ergocalciferol; 50 000 IU, 1.25 mg). The
slight
increase in the obese group was not significant. *Significant
time-by-
group interaction, P < 0.05 (ANOVA).
FIGURE 4. Correlation between BMI and peak serum vitamin
D2
(ergocalciferol) concentrations in the control (�) and obese (�)
groups
after oral intake of vitamin D2 (50 000 IU, 1.25 mg). The
correlation
coefficient (r = �0.56) was highly significant (P = 0.007).
abstract/72/3/690/4729361
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ingested orally, obese and nonobese subjects were challenged
with an oral dose of 50 000 IU vitamin D2. There was no
relation
between basal vitamin D2 concentrations and 25(OH)D. Peak

blood concentrations of vitamin D2 were not significantly
differ-
ent between the obese and nonobese subjects. However, BMI
was inversely correlated with peak blood vitamin D2 concentra-
tions. Thus, the orally supplied vitamin D2 was more bioavail-
able, probably because after absorption into the lymphatic
system
and transfer into the bloodstream, it is also sequestered in the
large pool of body fat.
Because humans obtain most of their vitamin D requirement
from casual exposure to sunlight, the > 50% decreased bioavail-
ability of cutaneously synthesized vitamin D3 in the obese
subjects could account for the consistent observation by us and
others that obesity is associated with vitamin D deficiency. Oral
vitamin D should be able to correct the vitamin D deficiency
associated with obesity, but larger than usual doses may be
required for very obese patients.
We thank B Hollis (Medical University of South Carolina,
Charleston) for
measuring the parathyroid hormone concentrations.
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14. Chen TC, Turner AK, Holick MF. A method for the
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VITAMIN D AND OBESITY 693
FIGURE 5. Correlation between BMI and peak serum vitamin
D3
(cholecalciferol) concentrations after whole-body irradiation
(27 mJ/cm2)
with ultraviolet B radiation in control (�) and obese (�)
subjects. The
correlation coefficient (r = 0.55) was highly significant (P =
0.003).
abstract/72/3/690/4729361
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on 02 March 2018

Evidence for alteration of the vitamin D-
endocrine system in obese subjects.
N H Bell, … , M J Oexmann, S Shaw
J Clin Invest. 1985;76(1):370-373. doi:10.1172/JCI111971.
Serum immunoreactive parathyroid hormone (PTH) is increased
in obese as compared with
nonobese subjects and declines with weight loss. To determine
whether alteration of the
vitamin D-endocrine system occurs in obesity and whether
ensuing secondary
hyperparathyroidism is associated with a reduction in urinary
calcium, a study was
performed in 12 obese white individuals, five men and seven
women, and 14 nonobese
white subjects, eight men and six women, ranging in age from
20 to 35 yr. Body weight
averaged 106 +/- 6 kg in the obese and 68 +/- 2 kg in the
nonobese subjects (P less than
0.01). Each of them were hospitalized on a metabolic ward and
were given a constant daily
diet containing 400 mg of calcium and 900 mg of phosphorus.
Whereas mean serum
calcium, serum ionized calcium, and serum phosphorus were the
same in the two groups,
mean serum immunoreactive PTH (518 +/- 48 vs. 243 +/- 33
pg/ml, P less than 0.001), mean
serum 1,25-dihydroxyvitamin D [1,25(OH)2D] (37 +/- 2 vs. 29
+/- 2, P less than 0.01), and
mean serum Gla protein (33 +/- 2 vs. 24 +/- 2 ng/ml, P less than
0.02) were significantly
higher, and mean serum 25-hydroxyvitamin D (25-OHD) (8 +/-
1 vs. 20 +/- 2 ng/ml, P less

than 0.001) was significantly lower in the obese than in […]
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Rapid Publication
Evidence for Alteration of the Vitamin D-Endocrine System in
Obese Subjects
Norman H. Bell, Sol Epstein, Anne Greene, Judith Shary, Mary
Joan Oexmann, and Sheryl Shaw
Veterans Administration Medical Center and Departments of
Medicine and Pharmacology, Medical University of South
Carolina,
Charleston, South Carolina 29403; Albert Einstein Medical
Center, Philadelphia, Pennsylvania 55901
Abstract
Serum immunoreactive parathyroid hormone (PTH) is increased

in obese as compared with nonobese subjects and declines with
weight loss. To determine whether alteration of the vitamin D-
endocrine system occurs in obesity and whether ensuing sec-
ondary hyperparathyroidism is associated with a reduction in
urinary calcium, a study was performed in 12 obese white
individuals, five men and seven women, and 14 nonobese white
subjects, eight men and six women, ranging in age from 20 to
35 yr. Body weight averaged 106±6 kg in the obese and 68±2
kg in the nonobese subjects (P < 0.01). Each of them were
hospitalized on a metabolic ward and were given a constant
daily diet containing 400 mg of calcium and 900 mg of
phosphorus. Whereas mean serum calcium, serum ionized
calcium, and serum phosphorus were the same in the two
groups, mean serum immunoreactive PTH (518±48 vs. 243±33
pg/ml, P <0.001), mean serum 1,25-dihydroxyvitamin D
I1,25(OH)2D] (37±2 vs. 29±2, P < 0.01), and mean serum
Gla protein (33±2 vs. 24±2 ng/ml, P < 0.02) were significantly
higher, and mean serum 25-hydroxyvitamin D (25-OHD) (8±1
vs. 20±2 ng/ml, P <0.001) was significantly lower in the
obese than in the nonobese men and women. Mean urinary
phosphorus was the same in the two groups, whereas mean
urinary calcium (115±10 vs. 166±13 mg/d, P < 0.01) was
significantly lower, and mean urinary cyclic AMP(3.18±0.43
vs. 1.84±0.25 nM/dl GF, P < 0.01) and creatinine clearance
(216±13 vs. 173±6 liter/d, P < 0.01) were significantly higher
in the obese than in the nonobese individuals. There was a
significant positive correlation between percentage of ideal
body weight and urinary cyclic AMP(r = 0.524, P < 0.01)
and between percentage of ideal body weight and serum
immunoreactive PTH (r = 0.717, P < 0.01) in the two groups.
The results provide evidence that alteration of the vitamin D-
endocrine system in obese subjects is characterized by
secondary
hyperparathyroidism which is associated with enhanced renal
tubular reabsorption of calcium and increased circulating
1,25(OH)2D. The reduction of serum 25-OHD in them is

attributed to feedback inhibition of hepatic synthesis of the
precursor by the increased serum 1,25(OH)2D.
Introduction
Available evidence indicates that serum immunorea
thyroid hormone (PTH)1 is higher in obese than it
Dr. Bell is a Veterans Administration Medical Investigai
reprint requests to Dr. Bell, VA Medical Center.
Received for publication 9 April 1985.
Lctive para-
n nonobese
young adults and declines with weight loss (1). In view of
these observations, we carried out an investigation to determine
whether obesity modifies the vitamin D-endocrine system and
whether secondary hyperparathyroidism is associated with a
reduction of urinary calcium in obese subjects.
Methods
26 normal white subjects were studied. There were 12 obese
individuals
(five men and seven women) and 14 nonobese subjects (eight
men
and six women) ranging in age from 20 to 35 yr. All of them
were
hospitalized on the General Clinical Research Center of the
Medical
University of South Carolina, Charleston, SC. They were given
only
distilled water to drink and a constant daily diet that was
estimated to

contain 400 mg of calcium, 900 mg of phosphorus, 18 meq of
magnesium, 110 meq of sodium, and 65 meq of potassium.
Fasting
blood samples were collected for measurement of serum
calcium,
ionized calcium, phosphorus, magnesium, creatinine, Gla
protein, 25-
hydroxyvitamin D (25-OHD), 1,25-dihydroxyvitamin D
[1,25(OH)2D],
and immunoreactive PTH. 24-h urines were collected for
measurement
of calcium, phosphorus, sodium, potassium, magnesium,
creatinine,
and cyclic AMP.
Serum and urinary calcium (2), phosphorus (3), creatinine (4),
and
magnesium (5) were measured by automated colorimetric
methods.
Serum ionized calcium was measured with a solid state ion
electrode.
Urinary sodium and potassium were determined by flame
photometer.
Serum 25-OHD was measured in duplicate at two concentrations
by
competitive protein binding with vitamin D-deficient rat serum
(6)
after extraction with acetonitrile, washing with phosphate
buffer,
chromatography on C-18 Sep-Pak, and elution with acetonitrile
(7).
25-OHD was separated from other vitamin D metabolites before
the
binding assay by chromatography on silica Sep-Pak and elution
with
hexane-propanol (94:6) (7). Serum 1,25(OH)2D was measured

by the
method of Reinhardt et al. (7). Serum immunoreactive PTH was
measured by radioimmunoassay with a COOH-terminal specific
anti-
body from chicken 77125 at a dilution of 1:10,000 (8). Serum
Gla
protein was determined by radioimmunoassay (9). Urinary
cyclic AMP
was measured by radioassay with a binding protein (10). Results
are
expressed as nM/dl glomerular filtrate (GF) (11).
Statistical analyses were performed with nonpaired t test and
correlation coefficient by standard methods. The percentage of
ideal
body weight was determined from tables of the Metropolitan
Life
Insurance Company, New York.
Results
Weights of the obese and nonobese subjects averaged 106±6
tor. Address and 68±2 kg, respectively (P < 0.01). The mean age
was
26±1 yr for the obese and 24±1 yr for the nonobese individuals.
_______ The results are summarized in Tables I and II and in
Fig.
1. Mean serum Gla protein, mean serum immunoreactive
1. Abbreviations used in this paper: GF, glomerular filtrate;
PTH,
parathyroid hormone.
370 N. H. Bell, S. Epstein, A. Greene, J. Shary, M. J. Oexmann,

and S. Shaw
J. Clin. Invest.
© The American Society for Clinical Investigation, Inc.
0021-9738/85/07/0370/04 $ 1.00
Volume 76, July 1985, 370-373
Table I. Serum Values in Obese and Nonobese White Subjects
Serum Serum Serum Serum Serum Serum Serum Serum
Subjects calcium Ca2+ phosphorus magnesium Gla protein*
iPTHt 25-OHD 1,25(OH)2D
mg/dl mg/dl mg/dl meqiliter ng/ml pg/mi ng/ml pg/mi
Obese (12) 9.0±0.1 4.8±0.1 4.0±0.1 1.88±0.02 33±2 518±48 8±1
37±2
Nonobese (14) 9.0±0.1 4.8±0.1 3.9±0.2 1.85±0.04 24±3 243±33
20±2 29±2
P value NS NS NS NS <0.02 <0.001 <0.001 <0.01
Results are given as mean±SE. Figures in parentheses are the
number of subjects. * Serum Gla protein was measured in 11
obese and 14
nonobese subjects. t Serum immunoreactive PTH (iPTH) was
measured in 12 obese and 13 nonobese subjects.
PTH, and mean serum 1,25(OH)2D were significantly higher
in the obese as compared to the nonobese men and women
(Table I). Mean serum calcium, serum ionized calcium, serum
phosphorus, and serum magnesium were the same in the two
groups. Mean serum 25-OHD was significantly lower in the
obese than in the nonobese individuals. During the 2 d on the
constant diet, mean urinary calcium was significantly lower in

the obese than in the nonobese subjects (Table II). Mean
urinary cyclic AMPand creatinine clearance were significantly
higher in the obese subjects, and mean urinary phosphorus,
potassium, and magnesium were the same in the two groups.
As shown in Fig. 1, in all subjects there was a significant
positive correlation between percentage of ideal body weight
and urinary cyclic AMP(r = 0.524, P < 0.01). There was also
a significant positive correlation between percentage of ideal
body weight and serum immunoreactive PTH (r = 0.717, P
< 0.01).
Discussion
Bone mass is increased (12-18) and urinary calcium is dimin-
ished (19) in black as compared with white individuals. We
previously demonstrated increases in mean serum immuno-
reactive PTH, serum 1,25(OH)2D, and urinary cyclic AMP,
and confirmed that mean urinary calcium is reduced in normal
nonobese blacks (20). Further, the demonstration that the
blacks excreted an intravenous calcium load (15 mg calcium/
kg body weight infused over 8 h) as efficiently as whites
provided evidence that the reduction in urinary calcium in
blacks was caused by increases in circulating PTH and not by
primary enhancement of tubular reabsorption of the cation.
Mean serum Gla protein, an index of PTH status (21), was
lower in blacks than in whites, despite the higher circulating
PTH in the blacks. We interpreted these results to indicate
that modification of the vitamin D-endocrine system, with
enhanced renal tubular reabsorption of calcium and increased
circulating 1,25(OH)2D caused by increases in serum PTH,
may contribute to the greater bone mass in blacks (20). The
larger bone mass in them is attributed to increased muscle
mass (13).
The present findings in obese white subjects are similar to

the ones obtained by us in nonobese blacks. Thus, obese white
individuals show increases in mean serum immunoreactive
PTH (1), serum 1,25(OH)2D, and urinary cyclic AMP, and
decreases in urinary calcium as compared with nonobese white
men and women. The reduction of urinary calcium in the
obese individuals is all the more evident since it occurred
despite an average increase of 24.8% in creatinine clearance.
Obese postmenopausal women were found to have a lower
urinary calcium-to-creatinine ratio as compared with nonobese
postmenopausal women (22). One difference for which we
have no explanation is the reduction of serum Gla protein in
blacks in our previous study and the increase of serum Gla
protein in the obese as compared with nonobese white subjects,
which was seen in the present investigation. Weinterpret our
results to indicate that alteration of the vitamin D-endocrine
system also occurs in obesity, and is characterized by secondary
increases in circulating PTH with consequent enhanced tubular
reabsorption in calcium and increased renal production of
1,25(OH)2D.
An alternative explanation for our findings in obese men
and women is impaired intestinal absorption of calcium. This
possibility appears unlikely, since malabsorption of calcium, if
prolonged, would lead to a decline in bone mass. In this
Table II. Urinary Values in Obese and Nonobese White Subjects
Urinary Urinary Urinary Urinary Urinary Urinary Creatinine
Subjects calcium phosphorus sodium potassium magnesium
cyclic AMP clearance
mg/d mg/d meqld meqld meqld nM/dI GF liter/d
Obese (12) 115±10 1,043±50 104±8 62±3 9.3±0.9 3.18±0.43
216±17
Nonobese (14) 166±13 938±37 124±8 62±4 9.2±0.4 1.84±0.25

173±6
P value <0.01 NS NS NS NS <0.01 <0.01
Obesity and the Vitamin D-Endocrine System 371
Results are given as mean±SE of the average of two consecutive
24-h urine values in each subject. Figures in parentheses are the
number of
subjects.
impaired production of 25-OHD in response to vitamin D
challenge described in the obese individuals (24). Low values
for serum 25-OHD were also observed in normal nonobese
black men and women in whom mean serum 1,25(OH)2D
was increased (20). It is likely that reduction of serum 25-
OHDin them results from impaired dermal production of
vitamin D because of increased skin pigment (27).
'' 80 100 120 140 160 180 200 220 240 260 Acknowledaments
IDEAL BODY WEIGHT%
Figure 1. Relationship between urinary cyclic AMPand
percentage
of ideal body weight in obese and nonobese white subjects. In
all of
them, there was a significant positive correlation between the
two
determinations (r = 0.524, P < 0.01). *, nonobese; o, obese.
regard, measurement of bone mass in obese subjects has
yielded conflicting results. Radiographic measurements of
metacarpal cortical area showed that skeletal mass was greater
in obese than in age-matched nonobese subjects (23). On the
other hand, bone mass of the forearm determined by single-

photon absorptiometry demonstrated values that were within
the normal range (24). Urinary calcium-to-creatinine ratio in
obese postmenopausal women, which was reduced as compared
with values in nonobese postmenopausal women, correlated
negatively with serum estrogen, and serum estrogens were
shown to correlate with body weight (22). It is possible,
therefore, that increases in circulating estrogen that occur in
obesity because of increased peripheral conversion from an-
drogens, could modify the skeletal response to PTH in obese
women (22). It is unlikely, however, that this phenomenon
accounts for changes in the vitamin D-endocrine system
observed in obese men.
As noted already, increased bone mass in blacks is thought
to result from an increased muscle mass (13). If greater strain
on the skeleton produced by the increased body weight dimin-
ishes the skeletal response to PTH in obesity, the elevated
serum immunoreactive PTH should decline with weight loss.
Atkinson et al. (1) followed 27 massively obese subjects for
periods of up to 1 yr after jejunal-ileal intestinal bypass, and
noted that serum immunoreactive PTH decreased with weight
loss. Indeed, the reductions in body weight and serum immu-
noreactive PTH paralleled each other. Thus, at 6 mo after
surgery there was a significant correlation between the amount
of weight loss, which averaged 44 kg, and the decrease in
serum immunoreactive PTH (1).
Mean serum 25-OHD was lower in the obese than in the
nonobese subjects. A reduction in mean serum 25-OHD was
also found in two other groups of obese individuals, one of
which had undergone jejunal-ileal bypass (24, 25). In these
subjects, there was a progressive increase in serum 25-OHD
after surgery to values that were in the normal range. In view
of the present findings, and the previously described decline
in elevation of serum immunoreactive PTH in association
with weight loss after intestinal bypass (1), we attribute the

low serum 25-OHD in obese subjects to feedback inhibition
of hepatic synthesis of the metabolite by increased circulating
1,25(OH)2D (26). Reversal of obesity and elevated serum
immunoreactive PTH would lead to a decline in serum
1,25(OH)2D and allow serum 25-OHD to return to values in
the normal range. This explanation would also account for the
We thank Elizabeth Katko for expert secretarial assistance, and
the
nursing, dietary, and laboratory staffs of the General Clinical
Research
Center for their contributions.
This work was supported in part by the Veterans Administration
and by grant MOI RR01070 (General Clinical Research Center)
from
the U. S. Public Health Service.
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Obesity and the Vitamin D-Endocrine System 373

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