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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online December 8, 2000 as doi:10.1096/fj.00-0584fje. |
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* The University of Tennessee, Knoxville, TN 37996-1900 and
The National Dairy Council®, Rosemont, IL 60018-5616
2Correspondence: University of Tennessee, 1215 West Cumberland Avenue, No. 229, Knoxville, TN 37996-1900. E-mail: mzemel{at}utk.edu
SPECIFIC AIMS
The present study was conducted to test the hypothesis that suppressing 1,25-(OH)2-D by increasing dietary calcium inhibits adipocyte [Ca2+]i, and thereby accelerates lipid catabolism and weight loss secondary to caloric restriction in aP2-agouti transgenic mice.
PRINCIPAL FINDINGS
1. Administration of basal low calcium diet caused an increase in
body weight, fat pad mass and basal adipocyte
[Ca2+]i in
aP2-agouti transgenic mice
Administration of a low-calcium (0.4%), high-fat, high-sucrose
diet to aP2-a mice for 6 wks resulted in a 
100% increase in
adipocyte [Ca2+]i (128±18 vs. 267±15 nM,
p<0.001), with a corresponding body weight gain of 29%
(p<0.001) and twofold increase in total fat pad mass
(p<0.001), demonstrating that diet-induced
dysregulation of adipocyte [Ca2+]i is
associated with diet-induced obesity and adiposity in aP2-a mice.
2. Administration of high-calcium diets caused a reduction in body
weight, fat-pad mass, and basal adipocyte
[Ca2+]i in energy-restricted
aP2-agouti transgenic mice
Increasing dietary calcium from CaCO3 (1.2% Ca
derived from CaCO3) or non-fat dry milk (1.2% or 2.4% Ca
derived from non-fat dry milk replacing 25% or 50% of protein,
respectively), caused a 50% decrease in adipocyte
[Ca2+]i (p<0.001,
Fig. 1
, lower panel), while caloric restriction exerted no effect on
adipocytes [Ca2+]i in mice maintained on the
basal low-calcium diet.
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Energy restriction on the low-calcium diet resulted in an 11%
body weight loss (p<0.001, Fig. 1
, upper panel),
compared with the ad lib group. However, markedly greater
weight reductions of 19%, 25%, 29% were observed in the
high-calcium, medium- and high-dairy groups, respectively
(p<0.01 vs. basal energy-restricted group, Fig. 1
).
Consistent with this finding, energy restriction caused only an 8%
decrease in fat pad mass on the low-calcium diet (not significant),
compared with the basal diet ad lib group. However, energy
restriction on the high-calcium diet caused a 42% decrease
(p<0.001, Fig. 2
, middle panel), which was further reduced by 60% and 69% by the
medium- and high dairy diets (p<0.001 vs. basal
energy-restricted group), respectively.
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3. Administration of high-calcium diets suppressed lipogenesis and
stimulated lipolysis in energy-restricted aP2-agouti
transgenic mice
Figure 2
(upper panel) demonstrates that the high-calcium
diet caused a 35% decrease in fatty acid synthase (FAS) activity
(p<0.05 vs. basal energy-restricted group), which
was further reduced by 63% and 62% by the medium- and high-dairy
diets (p<0.05), respectively. Similarly, the three
high-calcium diets caused corresponding decreases in adipocyte FAS
mRNA, with 61%, 72%, and 81% reductions on high-calcium, medium-
dairy and high-dairy diets, respectively (p<0.05 vs.
basal energy-restricted group, Fig. 3
, middle panel). Increasing dietary calcium caused marked increases
in lipolysis. Although the basal energy-restricted diet did not
affect adipocyte lipolysis, the high-calcium diet caused a 77%
stimulation of lipolysis (p<0.05, Fig. 2
, lower
panel), which was increased further by more than twofold in the medium-
and high-dairy diet groups (p<0.05 vs. basal
energy-restricted group). Increased lipolysis, coupled with decreased
lipogenesis, may represent a metabolic state in which the efficiency of
energy metabolism is shifted from energy storage to energy expenditure.
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4. Administration of high calcium diets promoted thermogenesis in
energy-restricted aP2-agouti transgenic mice
This shift in energy metabolism was confirmed further by
dietary calcium-induced increase in core temperature. All three
high-calcium diets exerted stimulatory effects on core temperature,
with 0.48°C, 0.57°C, and 0.67°C increases on the high-calcium,
medium -dairy and high-dairy diets, respectively
(p<0.05), while the basal energy-restricted diet did
not affect core temperature. A possibly physiological basis underlying
the increased core temperature is that the expression of uncoupling
protein 2 (UCP2), which has been implicated in thermogenesis, was
up-regulated in white adipose tissue, with 80% increase on all three
high-calcium diets (p<0.05).
CONCLUSIONS
Obesity is closely related to other metabolic disorders, including insulin resistance/hyperinsulinemia, hypertension, and cardiac hypertrophy. These diseases are integrated into a metabolic syndrome referred to as ‘Syndrome X’. To explain these tightly interacting abnormalities, Resnick proposed a unifying ‘ionic hypothesis,’ in which a common cell lesion underlying these disorders in different tissues was characterized, in part, by elevations in steady-state [Ca2+]i levels.
We have previously demonstrated that increasing adipocyte [Ca2+]i via activation of either receptor or voltage-mediated calcium channels stimulates expression and activity of FAS, a key enzyme in de novo lipogenesis, and inhibits basal and agonist-stimulated lipolysis in both human and murine adipocytes. Therefore, increasing [Ca2+]i appears to promote triglyceride storage in adipocytes by exerting coordinated control over lipogenesis and lipolysis and serving to simultaneously stimulate the former and suppress the latter, and thereby cause lipid filling.
Other endocrine and/or paracrine hormones that modulate human adipocyte [Ca2+]i also modulate adipocyte lipid metabolism. Agouti protein, an obesity gene product that is expressed in human adipose tissue and stimulates Ca2+ influx, simultaneously stimulates the expression and activity of FAS and inhibits basal and agonist-stimulated lipolysis via a Ca2+-dependent mechanism. Moreover, we recently demonstrated that agouti expression is highly correlated with in vivo FAS expression and activity in human adipose tissue, suggesting that agouti protein, a physiological Ca2+ agonist, may play a role in human obesity. In addition, we have recently reported that the calcitrophic hormone 1,25-(OH)2-D, which has been previously shown to stimulate [Ca2+]i in both vascular smooth muscle cells and pancreatic ß cells and to play a role in development of hypertension and hyperinsulinemia, respectively, also acts on human adipocytes to cause a sustained increase in [Ca2+]i and a corresponding marked inhibition of lipolysis. Further, several lines of evidence demonstrate that circulating 1,25-(OH)2-D level is increased in obese humans, which further suggests that increased 1,25-(OH)2-D may exert effects in human obesity in vivo.
Accordingly, antagonism of [Ca2+]i by inhibiting Ca2+ agonists is an attractive and logical approach for development of therapeutic intervention in obesity. In present study, antagonism of [Ca2+]i was achieved through a dietary intervention, increasing dietary calcium. This approach has previously been demonstrated to suppress 1,25-(OH)2-D levels in multiple studies. Accordingly, we proposed that dietary calcium suppression of 1,25-(OH)2-D would reduce adipocyte [Ca2+]i and thereby inhibit triglyceride accumulation.
Although Metz et al. and Bursey et al. previously reported that increased dietary calcium reduced body weight and body-fat composition in spontaneously hypertensive rats, Wistar-Kyoto rats, and lean and obese Zucker rats, they were unable to demonstrate the mechanism involved in this adiposity modulation. Although some investigators have attributed the effect of dietary calcium on lipid metabolism to potential inhibition of dietary fatty acid absorption, significant feed caloric losses do not result from moderate increases in dietary calcium. Indeed, data presented in this study demonstrate that increasing dietary calcium inhibits adipocyte [Ca2+]i, thereby facilitating weight loss by simultaneously stimulating lipolysis and inhibiting lipogenesis in energy-restricted aP2-a transgenic mice. Consistent with this finding, we previously found that increasing dietary calcium attenuated the development of diet-induced obesity in aP2-agouti transgenic mice.
Increasing dietary calcium resulted in increased adipocyte lipolysis and suppression of lipogenesis, similar to our observations in the present study. Accordingly, these data extend our previous observations by demonstrating that dietary calcium not only attenuates diet-induced obesity but also accelerates weight loss and fat mass reduction secondary to caloric restriction in established obesity. It is noteworthy that dairy and elemental calcium exerted qualitatively comparable effects; however, quantitatively, the effects were significantly different. Calcium in the form of dairy exerted a markedly greater effect on lipid metabolism and corresponding body-weight/adipose tissue mass reduction compared with a like quantity of elemental calcium. The reason for this difference is not yet apparent, although it is consistent with our previous observations.
It is interesting that dietary calcium not only modulates lipid metabolism involved in lipogenesis and lipolysis, but also causes an increased expression of white adipose tissue UCP2 (which has been implicated in thermogenesis), and a corresponding higher core temperature, an indirect metabolic index associated with thermogenesis. Although the contribution of thermogenesis to anti-obesity action of Ca2+ channel blockade has been addressed in previous studies, this mechanism remains controversial in that some investigators have attributed the thermogenic effect of Ca2+ channel blockade to the increased function of brown adipose. In fact, we have also observed previously an increased core temperature in agouti-overexpressing Avy mice treated with the L-type Ca2+ channel antagonist nifendipine. Although this action was inexplicable at the time, our present data in this study suggest that up-regulation of UCP2 expression may be responsible. However, further study is required to address the precise mechanism whereby dietary calcium regulates UCP2 expression. Although this up-regulation of UCP2 expression may result directly from inhibition of [Ca2+]i, it is also possible that it is merely a result of increased substrate (fatty acid) flux secondary to increased lipolysis.
In summary, high-calcium diets exert potent effects in enhancing reduction of body weight and fat pad mass in energy-restricted aP2-agouti transgenic mice. High-calcium diets suppressed adipocyte [Ca2+]i, stimulated lipolysis, inhibited lipogenesis, and caused an increased white adipose tissue UCP2 expression and a corresponding increase in core temperature. Consequently, dietary calcium facilitates reduction of fat tissue mass and body weight in kilocalorie restriction by modulating energy metabolism, which serves to reduce energy storage and increase thermogenesis. These data may provide a useful framework for further development of effective dietary intervention in obesity.
FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.00-0584fje To cite this article, use (December 8, 2000) FASEB J. 10.1096/fj.00-0584fje 
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