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* Department of Nutrition, The University of Tennessee, Knoxville, Tennessee 37996-1900, USA; and
The National Dairy Council, Rosemont, Illinois 60018-5616, USA
1Correspondence: Department of Nutrition, The University of Tennessee, 1215 W. Cumberland Ave., Room 229, Knoxville, TN 37996-1900, USA. E-mail: mzemel{at}utk.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Key Words: human adipocytes· • lipolysis • agouti • PTH
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2
3)
. Recombinant agouti protein, an obesity
gene product, stimulates Ca2+ influx in a variety
of cells (4
, 5)
. Agouti also stimulates the expression and
activity of fatty acid synthase, a key enzyme in de novo
lipogenesis, and inhibits basal and agonist-stimulated lipolysis in
human and murine adipocytes via a Ca2+-dependent
mechanism (6
, 7)
. These effects can be mimicked in the
absence of agouti by either receptor or voltage-mediated
Ca2+ channel activation and inhibited by
Ca2+ channel antagonism (6
7
8)
;
agouti-induced obesity in transgenic mice was markedly attenuated by 4
wk of Ca2+ channel antagonism (9)
.
Thus, increasing adipocyte intracellular Ca2+
appears to promote triglyceride storage in human adipocytes by exerting
a coordinated control of lipogenesis and lipolysis, serving to
simultaneously stimulate the former and inhibit the latter.
During the course of a previous, unrelated clinical trial investigating
the antihypertensive effect of calcium in obese African-Americans, we
noted that increasing daily calcium intake from ~400 to 1000 mg/day
for 1 year resulted in a 4.9 kg reduction in body fat (Fig. 1
). Although these data were inexplicable at the time, our recent data
demonstrating regulation of adipocyte energy storage by intracellular
Ca2+ lead to the proposal that increases in
circulating calcitrophic hormones [1,25-(OH)2-D
and/or parathyroid hormone] secondary to low calcium diets stimulate
adipocyte Ca2+ influx and thereby increase lipid
storage. If this is correct, then increasing dietary calcium should
suppress calcitrophic hormones and thereby reduce adipocyte
intracellular Ca2+ and lipid storage. The present
study was conducted to address this concept.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 17)
and cultured in Dulbecco’s modified Eagle’s
medium supplemented with 1% fetal bovine serum, penicillin (100
IU/ml), streptomycin (100 µg/ml), and gentamicin (50 µg/ml).
Approval for this procedure was obtained from the Institutional Review
Board for Human Subjects of the University of Tennessee. Cells were
cultured in suspension and maintained in a thin layer at the top of the
culture media, which was changed every day. Cells were studied ~72 h
after isolation and were serum-starved prior to study.
Animals and diets
To evaluate the role of dietary calcium in regulating adiposity
in vivo, transgenic mice expressing agouti
specifically in adipocytes under the control of the aP2 promoter were
studied. We have previously reported a characterization of these
animals. Briefly, they exhibit a normal pattern of leptin expression
and activity similar to that found in humans and exhibit a human
pattern (adipocyte-specific) of agouti expression
(10)
. We have found these mice to be useful models for
diet-induced obesity in that they are not obese on a standard AIN-93G
diet, but become obese in response to hyperinsulinemia induced by
either insulin administration (10)
or high sucrose diets
(11)
. Male aP2-agouti transgenic animals from our colony
were placed at 6 wk of age on a modified AIN 93-G diet with suboptimal
calcium (0.4%), sucrose as the sole carbohydrate source, and fat
increased to 25% of energy with lard. They were randomized to four
groups, as follows. The basal group continued this diet with no
modifications; a high calcium group received the basal diet
supplemented with CaCO3 to increase dietary
calcium by threefold to 1.2%; a medium dairy diet, in which 25% of
the protein was replaced by non-fat dry milk and dietary calcium was
increased to 1.2%; and a high dairy group in which 50% of the protein
was replaced by non-fat dry milk, increasing calcium to 2.4%. Food
intake and spillage was measured daily, and animals were weighed
weekly. At the conclusion of the 6 wk feeding period, animals were
killed by exsanguination under isoflurane anesthesia, and blood was
collected via cardiac puncture for glucose and insulin measurements.
Fat pads (epididymal, perirenal, abdominal, and subscapular) were
dissected, immediately weighed, frozen in liquid nitrogen, and stored
at -80°C. Fatty acid synthase activity and mRNA levels were measured
in abdominal fat as described below.
Core temperature
Core temperature was used as an indirect metabolic index to
determine whether any reduction in efficiency of conversion of food
energy to body weight was accompanied by increased thermogenesis
(9)
. Temperature was measured via a thermocouple (Columbus
Instruments, Columbus, Ohio). The probe was inserted a constant
distance (1.8 cm) into the rectum of each animal. After stabilization
(10 s), the temperature was recorded every 5 s for 30 s
(9)
. All temperature measurements were made between 8:00
and 9:00 A.M.
Intracellular calcium (human adipocytes)
Intracellular Ca2+ was determined
fluorometrically as described previously (17)
. Cells were
washed with HEPES-buffered salt solution loaded with
Fura-2-acetoxymethyl ester (10 µM) for 45 min at 37°C in the dark
with continuous shaking. Cells were then rinsed three times,
resuspended, and intracellular Ca2+ was measured
using dual excitation (340 and 380 nm)/single emission (510 nm)
fluorometry. After the establishment of a stable baseline, the response
to 1,25-(OH)2-D or parathyroid hormone (10 pM-100
nM) or their respective vehicles was determined. Digitonin (25 µM)
and Tris/EGTA (100 mM, pH 8.7) were used to for calibration to
calculate the final intracellular Ca2+
(18)
.
Lipolysis
Adipocytes were incubated for 4 h in the presence or
absence of forskolin (1 µM), and glycerol release into the culture
medium was measured (18)
to assess lipolysis. Glycerol
release data was normalized for cellular protein.
Fatty acid synthase activity and mRNA levels
Immediately after death, adipose tissue was isolated and fatty
acid synthase activity was measured in cytosolic extracts by measuring
the oxidation rate of NADPH, as described previously (6
, 9
, 17)
. Enzyme activity was protein corrected using Coomassie blue
dye.
Total RNA was extracted by cesium chloride density gradient,
electrophoresed, subjected to Northern blot analysis, and hybridized
with a radiolabeled rat cDNA probe for fatty acid synthase using
standard methods (6
, 12
, 17)
. Autoradiographs were
quantitated densitometrically, and all blots were stripped and reprobed
with ß-actin as a loading control.
Statistical analysis (in vitro and animal data)
All data are expressed as mean ± SD. Data were
evaluated for statistical significance by one-way analysis of variance
(ANOVA) or t test, depending on the number of comparisons
made. All data sets with multiple comparisons were analyzed via ANOVA,
followed by separation of significantly different group means via test
the least significant difference using SPSS-PC (v. 8.0).
NHANES III analysis
To determine whether the animal observations are relevant in
defining a role for dietary calcium in modulating body composition at
the population level, an analysis of the National Health and Nutrition
Examination Survey (NHANES III) data set was conducted. This large
cross-sectional survey conducted between 1988 and 1994 followed a
complex, four-stage probability sampling scheme (13)
designed to represent the entire U.S. civilian noninstitutionalized
population over the age of 2 months. Only adults completing all three
phases of the study (interview, physical examination, and laboratory
examination) were included in this data analysis; respondents were
excluded from this analysis if they could not provide complete, usable
body composition/anthropometric data (e.g., amputees and individuals
wearing casts), used insulin, or were pregnant, recently pregnant, or
currently breast-feeding. Body composition was assessed using the
anthropometric and bioelectrical impedance data collected during the
physical examination, with percent body fat calculated using the
regression equations derived by Segal (14)
.
Odds ratios for percent body fat and corresponding 95% confidence
intervals were estimated by multiple logistic regression analysis with
a robust variance estimation method using SUDAAN (15)
.
Point estimates for all parameters were weighted to reflect the
population distribution of each; variances were calculated using SUDAAN
(15)
to take the complex sampling design into account, as
failure to account for the weighting and design effects of a complex
sample design will result in distortion of estimates and
underestimation of variance. Analyses were conducted separately for men
and women, and all odds ratios were adjusted for age by including age
in the model as a continuous variable. Other covariates included in the
model were caloric intake, race/ethnicity, and activity level.
Characteristics of the study sample are shown in Tables 1
and
2
.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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demonstrates that both 1,25-(OH)2-D and
parathyroid hormone (PTH) stimulate significant, sustained increases in
intracellular Ca2+ in primary cultures of human
adipocytes (P<0.001; EC50 ~ 50 pM
for 1,25-(OH)2-D and ~10 nM for PTH).
1,25-(OH)2-D treatment also resulted in marked
(83%) inhibition of forskolin-stimulated lipolysis
(P<0.001) in human adipocytes (Fig. 3
). PTH treatment exerted little effect on lipolysis (data not shown)
despite its stimulation of an intracellular Ca2+
response, most likely as a result of an accompanying activation of
adenylate cyclase.
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Treatment of aP2-transgenic-agouti mice with the high fat/high sucrose
basal diet resulted in a weight gain of 24%, which was reduced by 26
and 29% by the high calcium and medium dairy diets, respectively
(P<0.04), and further reduced by 39% by the high dairy
diet (P<0.04; Fig. 4
). These differences occurred despite the lack of any difference in food
intake. Measurement of core temperature, an indirect metabolic index,
reflected these observations, with ~0.5°C increases in core
temperature in response to all three high calcium diets
(P<0.03; Fig. 5
). This increase, coupled with the lack of difference in food intake, is
indicative of a shift in efficiency of energy metabolism from energy
storage to thermogenesis.
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This shift in energy metabolism was evident in studies of fatty acid
synthase, a key enzyme in de novo lipogenesis that is highly
sensitive to regulation by nutrients and hormones (12)
.
The basal diet caused a 2.6-fold increase in fatty acid synthase
activity, and this effect was markedly attenuated by all three high
calcium diets (P<0.002; Fig. 6A
). The diets caused corresponding decreases in adipocyte
fatty acid synthase mRNA, with a 27% reduction on the high calcium
diet and a 51% reduction on the medium and high dairy diets
(P<0.01; Fig. 6B
). Adipocyte lipolysis responded
to dietary manipulations in an inverse fashion to the fatty acid
synthase responses. The basal diet caused a marked (67%) suppression
of lipolysis (P<0.0001); however, lipolysis was stimulated
3.4- to 5.2-fold by the high calcium diets (P<0.015; Fig. 6C
), with greater effects from the high dairy diets than from the high
calcium diet. Assessment of fat pad mass after 6 wk of dietary
treatment provides further support for these findings. Table 3
demonstrates that all three high calcium diets caused a 36% reduction
in mass of the epididymal, abdominal, perirenal, and subscapular
adipose tissue compartments (P<0.001). Epidymal and
subscapular fat pad mass was reduced by ~50% by all three diets,
whereas the abdominal fat pads exhibited greater decreases on the
medium and high dairy diets than on the high calcium diet
(P<0.001; Table 3
).
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Serial measurements of plasma glucose and insulin demonstrate a
diabetogenic effect of the basal high fat/high sucrose/low calcium
diet, with an increase in fasting glucose from 98 ± 10 to
130 ± 11 mg/dl (P<0.02) and a corresponding degree of
compensatory hyperinsulinemia. These increases were attenuated by the
high calcium and medium dairy diets and prevented by the high dairy
diet (Fig. 7
).
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Table 4
summarizes the NHANES III data analysis. After controlling for energy
intake, activity level, age, race, and ethnicity, the odds ratio of
being in the highest quartile of body fat was markedly reduced from
1.00 for the first quartile of calcium intake to 0.75, 0.40, and
0.16 for the second, third, and fourth quartiles, respectively
(multiple R2=0.20; P=0.0009), in adult
women. Similarly, the regression model for males demonstrated an
inverse relationship between calcium and dairy intakes and body fat
(multiple R2=0.40; P=0.0006), although
a comparable dose-responsive reduction in relative risk (odds ratio) by
quartile of calcium intake was not evident from the model.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, 5)
and promotes energy storage in human
adipocytes by coordinately stimulating the expression and activity of
fatty acid synthase, a key enzyme in de novo lipogenesis and
inhibiting lipolysis in a Ca2+-dependent fashion
(6
, 7)
. The carboxyl terminus of agouti protein, which
retains functional activity in an in vitro assay system
(20)
, bears a striking spatial homology in number and
spacing of cysteine residues to spider and snail venoms
(
-conotoxins, plectoxins), which target Ca2+
channels (21)
. Moreover, this agouti modulation of
adipocyte lipid metabolism is fully mimicked by
Ca2+ channel agonists and inhibited by
Ca2+ channel antagonists (6
7
8)
. In
addition, treating transgenic mice overexpressing agouti
with a Ca2+ channel antagonist (nifedipine) for 4
wk resulted in significant decreases in adipocyte lipogenesis and an
18% reduction in adipose tissue mass (9)
. Thus, adipocyte
Ca2+ modulates energy storage, suggesting that
adipocyte Ca2+ is a logical target for
pharmacological and/or nutritional regulation of adiposity.
Dietary calcium modulation of intracellular calcium, mediated by
suppression of calcitrophic hormones, has previously been demonstrated
to attenuate the risk of hypertension, and possibly type II diabetes as
well (23
, 24)
. Intracellular calcium plays a key role in
multiple related metabolic disorders, including hypertension, cardiac
hypertrophy, insulin resistance, and hyperinsulinemia, all of which are
commonly associated with obesity. It is now well recognized that these
are not merely co-morbid factors that occur secondary to obesity, but
rather are part of an integrated metabolic syndrome referred to as
‘syndrome X’ (25)
, ‘plurimetabolic syndrome’, the
‘deadly quartet’ (obesity, hypertriglyceridemia, hypertension and
insulin resistance/hyperinsulinemia), or ‘generalized cardiovascular
and metabolic disease’ (23
, 24)
. Regardless of
terminology, a growing body of evidence suggests that these conditions
are all characterized by an underlying impairment in intracellular
Ca2+ (1
2
3
, 23
, 24
, 26
27
28)
. Indeed,
Resnick (23)
has proposed a unifying ‘ionic hypothesis’
in which the varying metabolic abnormalities associated with syndrome X
represent different tissue-specific manifestations of a cellular lesion
characterized, in part, by elevations in steady-state intracellular
Ca2+ levels. Consistent with this concept,
correcting elevations in intracellular Ca2+
results in clinical improvements in blood pressure, insulin resistance,
platelet aggregation, and left ventricular hypertrophy
(23)
. Our previous studies of the mechanisms of
agouti-induced obesity indicate that obesity may also be partly a
manifestation of a ‘lesion’ in intracellular
Ca2+ regulation (4
5
6
7
, 9)
; data from
the present study lend further support for this hypothesis.
For adipocyte Ca2+ to serve as a logical
target for nutritional regulation, human adipocytes would need to
exhibit responsiveness to calcitrophic hormones. Our observation in the
present study that human adipocytes respond to both parathyroid hormone
and 1,25-(OH)2-D with dose-responsive increases
in intracellular Ca2+ suggests that low
Ca2+ diets, by virtue of stimulating a
calcitrophic hormone response, will increase adipocyte intracellular
Ca2+ whereas higher calcium diets will suppress
this response. Accordingly, a coordinated down-regulation of
lipogenesis and up-regulation of lipolysis would be predicted to result
from increasing dietary calcium. Data from the present study of
transgenic mice overexpressing agouti in adipose tissue to
mimic the human pattern of expression support this prediction, as the
obesity-promoting effects of the lard/sucrose-based diet were
significantly attenuated on the high calcium and high dairy diets.
These data are further supported by the measurements of fatty acid
synthase mRNA and activity, as well as the lipolysis data. Thus, these
data demonstrate that increasing dietary calcium attenuates
diet-induced adiposity by modulating adipocyte intracellular
Ca2+ and thereby coordinately regulating
lipogenesis and lipolysis (6
7
8
9)
.
Dairy and elemental sources of calcium exerted qualitatively comparable
effects; however, calcium in the form of dairy exerted a greater effect
on attenuating fat deposition than a comparable quantity of elemental
calcium. Consistent with this, a recent randomized clinical trial
demonstrated a markedly greater weight loss (7.0 vs. 1.7 kg) in
patients maintained on a milk-based diet for 16 wk vs. those maintained
on conventional hypocaloric diet at the same level of energy intake
(16)
. Although this difference was attributed to the
novelty of the milk-based diet possibly contributing to a greater level
of compliance, data presented herein suggest that this effect may also
be attributable to suppression of 1,25-(OH)2-D
and adipocyte Ca2+, with a consequent reduction
in the efficiency of energy utilization. This concept is supported by
our population-based observations in NHANES III. These data demonstrate
a profound reduction in the odds of being in the highest quartile of
adiposity associated with increases in calcium and dairy product
intake. This analysis was controlled for both energy intake and
physical activity. Thus, these data indicate that, for any given level
of energy intake and expenditure, a low calcium diet favors increased
adipose tissue energy storage, but the converse was true for higher
calcium diets. Accordingly, dietary calcium appears to modulate the
efficiency of energy utilization, with low calcium diets favoring
increased efficiency of energy storage and higher calcium diets
reducing energy efficiency and instead favoring increased
thermogenesis. This concept is further supported by our observation of
reduced energy efficiency and increased core temperature in the
transgenic mice fed the higher calcium diets.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-melanocyte-stimulating hormone receptor antagonist. Biochemistry 34,12341-12346
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