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Journal of the American College of Nutrition, Vol. 21, No. 2, 146S-151S (2002)
Published by the American College of Nutrition

Review

Regulation of Adiposity and Obesity Risk By Dietary Calcium: Mechanisms and Implications

Michael B. Zemel, PhD

The University of Tennessee, Knoxville, Tennessee

Address reprint requests to: Michael B. Zemel, Ph.D., The University of Tennessee, 1215 W. Cumberland Ave., Room 229, Knoxville, TN 37996. E-mail: mzemel{at}utk.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 REFERENCES
 
Dietary calcium plays a pivotal role in the regulation of energy metabolism; high calcium diets attenuate adipocyte lipid accretion and weight gain during periods of overconsumption of an energy-dense diet and increase lipolysis and preserve thermogenesis during caloric restriction, thereby markedly accelerating weight loss. Intracellular Ca2+ has a key role in regulating adipocyte lipid metabolism and triglyceride storage, with increased intracellular Ca2+ resulting in stimulation of lipogenic gene expression and lipogenesis, suppression of lipolysis, and increased lipid filling and adiposity. Moreover, we have recently demonstrated that the increased calcitriol released in response to low calcium diets stimulates Ca2+ influx in human adipocytes and thereby promotes adiposity. Accordingly, suppressing calcitriol levels by increasing dietary calcium is an attractive target for the prevention and management of obesity. In support of this concept, transgenic mice expressing the agouti gene specifically in adipocytes (a human-like pattern) respond to low calcium diets with accelerated weight gain and fat accretion, while high calcium diets markedly inhibit lipogenesis, accelerate lipolysis, increase thermogenesis and suppress fat accretion and weight gain in animals maintained at identical caloric intakes. Further, low calcium diets impede body fat loss, while high calcium diets markedly accelerate fat loss in transgenic mice subjected to caloric restriction. These findings are further supported by clinical and epidemiological data demonstrating a profound reduction in the odds of being obese associated with increasing dietary calcium intake. Notably, dairy sources of calcium exert a significantly greater anti-obesity effect than supplemental sources in each of these studies, possibly due to the effects of other bioactive compounds, such as the angiotensin converting enzyme inhibitor found in milk, on adipocyte metabolism, indicating an important role for dairy products in the control of obesity.

Key words: adipocyte, calcium, dairy, obesity, vitamin D

Key teaching points:

• Dietary calcium modulates 1,25-diydroxyvitamin D, which regulates intracellular calcium levels in adipocytes.

• Reducing 1,25-diydroxyvitamin D levels by increasing dietary calcium results in reduction of fat mass in the absence of caloric restriction in mice.

• This anti-obesity effect of dietary calcium is supported by human clinical and epidemiological studies.

• Dairy sources of calcium are markedly (50% to 100%) more effective than supplemental calcium in reducing adipose tissue mass.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
REFERENCES
 
Intracellular calcium plays a key role in regulating the target tissues involved in hypertension, insulin resistance and obesity, and dysregulation of intracellular calcium flux and/or signaling may represent a fundamental factor linking these three conditions. The observation that regulation of intracellular calcium in key disease-related target tissues occurs, in part, via calcitrophic hormones, which are under the control of dietary calcium, provides insight into the potential for modulation of both cardiovascular and metabolic disease risk by dietary calcium.

Dietary calcium is now well recognized to play an important role, beyond its importance in the maintenance of skeletal integrity, in modulating chronic disease risk. Dietary calcium modulation of blood pressure regulation is now incontrovertibly established through numerous well controlled studies over the last 20 years [1], and the practical relevance of this was clearly confirmed in the DASH (Dietary Approaches to Stop Hypertension) trial, which demonstrated that increasing low-fat dairy product and fruit and vegetable consumption exerted profound effects on blood pressure [1,2]; notably, dairy sources of calcium exert approximately twofold greater, and more consistent, effects than that found with supplements [3]. An accumulating body of evidence now suggests that dairy-rich diets not only reduce the risk of hypertension and cardiovascular disease, but may play an important role in the prevention and treatment of obesity as well.

We first became aware of this relationship when, during the course of conducting a clinical trial of the antihypertensive effect of calcium in obese African-Americans, we noted that increasing dietary calcium from ~400 to ~1,000 mg/day for one year resulted in a 4.9 kg reduction in body fat (Fig. 1). Indeed, there have been several isolated reports of an inverse relationship between dietary calcium, serum calcium and indices of obesity over the last 18 years, but in the absence of a conceptual basis for this relationship, it was not pursued. For example, in his evaluation of the relationship between blood pressure and nutrient intake, McCarron [4] noted a significant inverse relationship between calcium intake and body weight. Further, data from the Nationwide Food Consumption Survey (1987–88) demonstrated that individuals with the lowest calcium intakes tended to have the highest body weights; moreover, African-Americans consume the lowest level of calcium and exhibit the greatest prevalence of obesity [5]. In addition, inverse correlations were reported between serum ionized Ca2+ and obesity body mass index [6,7]. Although the data were inexplicable at the time of these reports, they have been recently re-evaluated and placed in a logical theoretical framework based upon our recent work describing the role of intracellular calcium in regulating adipocyte lipid metabolism and lipogenic gene expression [8]. This work, described below, suggests that calcium-rich diets produce significant metabolic effects which result in reduction of the risk of obesity and associated co-morbidities.



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  		Fig. 1. Loss of body fat in obese African-American adults on yogurt supplemented diet.

 
Role of Adipocyte Intracellular Ca2+
The framework for understanding an "anti-obesity" effect of dietary calcium derives from studies of the mechanism of action agouti, an obesity gene expressed in human adipocytes. We have demonstrated that agouti protein stimulates calcium influx [9,10] 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 calcium-dependent fashion [11,12]. This action of agouti was fully mimicked by calcium channel agonists and inhibited by calcium channel antagonists [11,12]. Moreover, treating transgenic mice overexpressing agouti with a calcium channel antagonist (nifedipine) for four weeks resulted in significant decreases in lipogenesis and in adipose tissue mass [13]. Thus, adipocyte calcium modulates energy storage and may be a logical target for interventions to control adiposity.

Role of Vitamin D
Accordingly, we considered the possibility that 1,25-dihydroxyvitamin D [1,25-(OH)2-D] may stimulate calcium influx in the adipocyte, as it does in vascular smooth muscle, leading to stimulation of lipogenesis, inhibition of lipolysis and expansion of adipocyte triglyceride stores. If so, suppressing 1,25-(OH)2-D levels by increasing dietary calcium would be predicted to inhibit adiposity and promote weight loss. Several lines of evidence have suggested a role for 1,25-(OH)2-D in obesity. Vitamin D receptor gene polymorphism is associated with susceptibility to obesity in patients with early onset type II diabetes [14], and circulating 1,25-(OH)2-D levels are elevated in obese individuals [15–20]. 1,25-(OH)2-D-induced hyperinsulinemia may also contribute to the development of obesity, as 1,25-(OH)2-D serves as an insulin secretagogue [21–23], and vitamin D receptor gene polymorphism influences insulin secretion and susceptibility to diabetes [24,25].

We recently reported that 1,25-(OH2)-D stimulates calcium influx, resulting in significant, sustained dose-responsive increases in steady state intracellular calcium in primary cultures of human adipocytes [8]. Moreover, 1,25-(OH2)-D treatment of human adipocytes resulted in a coordinated activation of fatty acid synthase (Fig. 2) and inhibition of lipolysis (Fig. 3 and 4), resulting in an expansion of adipocyte triglyceride stores, similar to the action of agouti on these cells [8]. These effects are mediated via a non-genomic, adipocyte membrane vitamin D receptor (mVDR) [26] similar to the mVDR recently identified in other tissues [27,28]. Consequently, suppression of 1,25-(OH2)-D with high calcium diets would be anticipated to reduce adipocyte intracellular Ca2+, and thereby decrease fatty acid synthase and increase lipolytic activity, thereby exerting an anti-obesity effect, as suggested above.



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  		Fig. 2. The effects of 1{alpha},25-(OH)2-D3 on fatty acid synthase in human adipocytes.

 


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  		Fig. 3. 1{alpha},25-(OH)2-D3 inhibits basal lipolysis in human adipocytes.

 


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  		Fig. 4. 1{alpha},25-(OH)2-D3 inhibits isoproterenol-stimulated lipolysis in human adipocytes.

 
Dietary Calcium Modulates Adiposity
This concept was confirmed in transgenic mice expressing agouti in adipose tissue under the control of the aP2 promoter, similar to the human pattern of expression. Mice placed on low calcium (0.4%)/high fat/high sucrose diets for six weeks exhibited marked increases in adipocyte lipogenesis, inhibited lipolysis and accelerated increases in body weight and adipose tissue mass. However, high calcium (1.2%) diets reduced lipogenesis by 51% and stimulated lipolysis three- to fivefold, resulting in 26% to 39% reductions in body weight and adipose tissue mass [8]. The magnitude of these effects depended upon the source of dietary calcium, with dairy sources of calcium exerting significantly greater effects than calcium carbonate.

The relevance of this finding at the population level was assessed via analysis of the U.S. National Health and Nutrition Examination Survey (NHANES III); odds ratios for percent body fat as a function of calcium intake were estimated by logistic regression, with age, race/ethnicity, activity level and caloric intake as covariates. The odds of being the highest quartile of body fat was reduced from 1.0 for the first quartile of calcium intake to 0.75, 0.40 and 0.16 for the second, third and fourth quartiles of calcium intake, respectively, for women [8]. The regression model for males similarly demonstrated a significant inverse relationship between dietary calcium and body fat, although the same simple dose-response relationship found in women was not evident [8].

Dietary Calcium Accelerates Weight and Fat Loss During Caloric Restriction
These data have significant implications for the prevention or attenuation of diet-induced obesity, but do not directly address the issue of whether high calcium diets will exert any effect on established obesity. Accordingly, a follow-up study was conducted to determine whether increasing dietary calcium will reduce metabolic efficiency and accelerate fat loss secondary to caloric restriction following dietary induction of obesity [29]. Administration of the same low calcium/high fat/high sucrose diet to aP2-agouti transgenic mice for six weeks resulted in a ~100% increase in adipocyte intracellular Ca2+ and a corresponding two-fold increase in total fat pad mass, demonstrating that dysregulation of adipocyte intracellular Ca2+ is associated with increased adiposity in aP2-agouti transgenic mice. The animals were then placed on energy restriction (70% of an ad libitum fed control group) for an additional six weeks. Energy restriction on the low calcium diet failed to reduce intracellular Ca2+ and only reduced body weight and fat pad mass by 11% and 8%, respectively. In contrast, energy restriction in conjunction with high calcium (1.2%) diets normalized intracellular calcium and resulted in 19% to 29% reductions in body weight and 42% to 69% decreases in fat pad mass, depending upon the calcium source (calcium carbonate versus dairy). Interestingly, the animals on the low calcium diets were unable to increase adipocyte lipolysis or suppress lipogenesis despite being on an energy-restricted regimen. In contrast, the high calcium diets caused marked reductions in fatty acid synthase expression and activity (35% to 81%), two- to threefold increases in lipolysis and increases in core temperature (0.48–0.67°C) and uncoupling protein-2 (UCP-2) expression during energy restriction [29]. These data demonstrate that high calcium diets suppress adipocyte intracellular Ca2+ by suppressing 1,25-(OH2)-D and thereby shifts the partitioning of dietary energy from energy storage to energy expenditure. Notably, dairy calcium (non-fat dry milk) was significantly more potent in inducing this shift, exerting approximately twice the effect of the calcium supplement on both adipocyte lipid metabolism and on body fat and body weight [29].

Role of Calcium versus Dairy in Augmenting Weight Loss
We have extended this work, using a calcium-fortified breakfast cereal as a calcium source to increase dietary calcium from 0.4% to 1.2%. The effects of the high calcium cereal were similar to those described above for calcium carbonate, producing significant attenuation of diet-induced obesity and accelerating weight and fat loss during caloric restriction [30]. However, the addition of a small amount of non-fat dry milk, sufficient to increase dietary calcium from 1.2% to 1.3% (with dietary macronutrients held constant) doubled the rate of fat loss [30]. Similarly, utilizing yogurt as a calcium source to increase dietary calcium from 0.4% to 1.2% (with compensatory adjustments in other diet components to ensure equivalent dietary macronutrient composition) resulted in marked augmentation of weight and fat loss compared to that found with calcium carbonate [31]. Thus, utilizing a dairy source of calcium is critical to maximizing the "anti-obesity" effects of calcium. Although the additional factor(s) in dairy responsible for this effect have not yet been identified, milk is recognized as a rich source of bioactive compounds [32], which may act independently or synergistically with the calcium to attenuate lipogenesis, accelerate lipolysis and/or affect nutrient partitioning between adipose tissue and skeletal muscle. Notably, milk proteins have been reported to contain significant angiotensin converting enzyme (ACE) activity [33,34]. Although ACE inhibitory activity may appear to be more relevant to an anti-hypertensive effect than to an anti-obesity effect of dairy, recent data demonstrates that adipocytes have an autocrine/paracrine renin-angiotensin system, and that adipocyte lipogenesis is regulated, in part, by angiotensin II [reviewed in 35]. Indeed, inhibition of the renin-angiotensin system mildly attenuates obesity in rodents, and limited clinical observations support this concept in hypertensive patients treated with ACE inhibitors [35].

Calcium/Vitamin D Modulation of Adipocyte Uncoupling Protein 2 and Metabolic Efficiency
In addition to calcium attenuating direct effects of 1,25-(OH2)-D on adipocyte lipid metabolism, a portion of the "anti-obesity" effect of dietary calcium may also be attributable to alterations in metabolic efficiency. As noted above, mice on high calcium diets exhibit increases in core temperature and in UCP-2 expression and decreases in the efficiency of energy utilization [8, 29, 30]. Although it is possible that this increase in UCP-2 expression is the result of increased fatty acid flux secondary to increased lipolysis, we have recently shown that 1,25-(OH2)-D exerts a direct, dose-responsive inhibitory effect on UCP-2 expression. Interestingly, this effect is independent of 1,25-(OH2)-D-mediated Ca2+ influx [26, 36] and the membrane vitamin D receptor, and is instead mediated via the nuclear vitamin D receptor (unpublished data). Thus, suppression of 1,25-(OH2)-D and consequent up-regulation of UCP-2 may contribute to our observation of decreased metabolic efficiency and increased thermogenesis in mice fed the high calcium diets. This effect, coupled with decreased lipogenesis and increased lipolysis secondary to decreased [Ca2+]i, may further contribute to the anti-obesity effect of dietary calcium (Fig. 5).



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  		Fig. 5. Mechanisms of the anti-obesity effect of dietary calcium.

 
Role of Calcium-Induced Fecal Fat Loss
Increasing dietary calcium may increase fecal fatty acid excretion and, accordingly, it is possible that the resultant increase in fecal energy loss could contribute to the anti-obesity effect of dietary calcium. However, clinical studies demonstrate that large increases in dietary calcium (2–4 g) result in statistically significant, but modest increases in fecal fat loss [37–39]. For example, a supplement of 2 g calcium (in the form of calcium carbonate) increased fecal fat excretion from 6.8% to 7.4% of total fat intake [38]. Although this contributes to net negative energy balance, this effect is too small to explain the observed anti-obesity effects of dietary calcium. Indeed, in order to achieve a clinically meaningful contribution to weight loss, orlistat must produce approximately a 30% inhibition of total dietary fat absorption, versus the approximately 1% inhibition found with dietary calcium. Thus, while calcium-inhibition of fat absorption may contribute to an anti-obesity effect, this effect appears too small to explain the observed effects; instead, the primary effect appears to be inhibition of 1,25-(OH)2-D effects on energy storage and utilization.

Clinical Data
Recent findings from other laboratories also support a beneficial role for calcium in weight control. In a two-year prospective study of 54 normal weight women participating in an exercise intervention, the dietary calcium:energy ratio was a significant negative predictor of changes in both body weight and body fat [40]; moreover, increased total calcium and dairy calcium intakes predicted fat mass reductions independently of caloric intake for women at lower energy intakes (below the mean of 1,876 kilocalories per day) [40]. A similar beneficial effect of dietary calcium on body fat mass accumulation has been demonstrated in growing children, as a significant inverse relationship between dietary calcium and body fat was recently reported in a five-year longitudinal study of preschool children (R2 = 0.51) [41].

Davies et al. have conducted a series of calcium intervention studies designed with primary skeletal endpoints, and have recently re-evaluated these data with a body weight endpoint [42]. The re-analysis involved 780 women who participated in five clinical trials (i.e., four observational and one double-blind, placebo-controlled randomized trial). They noted significant negative associations between calcium intake and body weight for all age groups (3rd, 5th and 8th decades of life), and an odds ratio for being overweight of 2.25 for young women in the lower half versus the upper half of calcium intake [42]. Data from the randomized controlled trial demonstrated a calcium treatment effect of 0.325 kg weight loss per year over four years with no intentional change in caloric intake; overall, the relationships derived from this re-analysis indicate that a calcium intake increase of 1,000 mg/day is associated with an 8 kg reduction in body weight [42].

Thus, accumulating data from experimental animal and human studies support a beneficial role for dietary calcium in weight management, with markedly greater effects evident from dairy versus non-dairy sources of calcium.

Received December 17, 2001.
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