Calcium Modulation of Adiposity

A substantial body of evidence has emerged over the last three years in support of what would superficially seem to be an unlikely concept: that dietary calcium plays a significant role in the modulation of energy metabolism and, consequently, exerts an “anti-obesity” effect (1, 2, 3). Increasing dietary calcium in the absence of caloric restriction seems to result in a repartitioning of dietary energy from adipose tissue to lean body mass, resulting in a net reduction in fat mass in both mice and humans (1, 2), whereas increasing dietary calcium intake during energy restriction results in a marked augmentation of body weight and fat loss in both mice and humans (1). These observations are supported by epidemiological observations from National Health and Nutrition Examination Survey III (NHANES III) (2), the Quebec Family Study (4), and the CARDIA study (5). Data from NHANES III demonstrate an 84% reduction in the probability of being in the highest quartile of body fat in those in the highest quartile vs. those in the lowest quartile of calcium and dairy intake (2). Similarly, data from the CARDIA study demonstrate a significant inverse relationship between dairy consumption and each of the components of the Insulin Resistance Syndrome (IRS), including obesity, during a 10-year follow-up of young adults who were overweight (body mass index ≥25 kg/m2) at baseline, with the odds of developing IRS 72% lower among overweight individuals in the highest (≥35 times per week) vs. the lowest (<10 times per week) category of dairy consumption; the cumulative incidence of obesity was reduced from 64.8% in the lowest dairy consuming group to 45.1% in the highest dairy consuming group (p < 0.001) (5). Papakonstantinou et al. (6) add to these observations in this issue of Obesity Research, demonstrating that high levels of dietary calcium significantly attenuate weight gain and total body fat accumulation in Wistar rats fed an obesigenic diet. These authors attribute their observations to calcium soap formation leading to a substantial increase in fecal loss of fatty acids and energy. This is consistent with clinical studies demonstrating that large increases in dietary calcium result in modest increases in fecal fat loss (7, 8). However, although this mechanism seems quantitatively sufficient to explain the body fat reduction in their study, the levels of fecal fat loss found in clinical trials of calcium supplementation may not be adequate to fully explain the weight and fat loss found in recent clinical and mouse studies of high calcium diets. For example, a 2 g calcium supplement increased fecal fat excretion from 6.8 to 7.4% of total fat intake (9); whereas this clearly contributes to negative energy balance, it is too small an effect to explain the anti-obesity effects of dietary calcium. Moreover, increasing dietary calcium intake was recently demonstrated to reduce adiposity in obesity-prone mice fed both low and high fat diets (10) although a markedly greater effect was noted on the high fat diet. This suggests that there are multiple mechanisms involved in this anti-obesity effect, with increased fecal fat loss playing a more prominent role in higher fat diets. Suppression of circulating 1, 25-dihydroxyvitamin D is an additional mechanism likely to play an important role in the anti-obesity effect of dietary calcium (reviewed in 3). Consistent with this, the article of Papakonstantinou et al. in this issue of Obesity Research (6) reports a remarkable 86% suppression of serum 1, 25-dihydroxyvitamin D levels in the rats fed the high calcium diet. 1, 25-dihydroxyvitamin D acts through a membrane vitamin D receptor to stimulate Ca2+ influx in both human and murine adipocytes (2, 3, 12), and intracellular Ca2+ has recently been shown to be a key regulator of adipocyte lipid metabolism, as increased intracellular Ca2+ stimulates lipogenic gene expression and activity and inhibits lipolysis, resulting in increased adipocyte lipid accumulation. Accordingly, suppression of 1, 25-dihydroxyvitamin D on high calcium diets causes a corresponding reduction in adipocyte lipid accumulation and overall adiposity (2, 3, 12), and this mechanism is likely to be predominant in lower-fat diets. Finally, it is notable that dairy sources of calcium exert significantly greater effects than elemental calcium on adiposity (1, 2, 3, 10, 11) in both mice and humans. Although the mechanism of this additional dairy effect is not yet clear, it seems to be a metabolic effect, rather than an effect on fecal energy losses (reviewed in 3). This is consistent with the recent report from the CARDIA study (5), in which the inverse relationship between dairy consumption and each of the components of the insulin resistance syndrome (including obesity) was explained by dairy intake and was not altered by adjustment for the calcium content of the diet, indicating an effect of dairy consumption independent of calcium intake. Thus, the work of Papakonstantinou et al. (6) published in this issue of Obesity Research serves to add to a now growing body of literature demonstrating a beneficial role of dietary calcium in regulating adiposity and highlights an additional mechanism (increased fecal lipid loss) likely to play a significant role in higher fat diets. However, in addition to the mechanisms highlighted here and in their report, there are clearly additional mechanisms yet to be identified that must be invoked to explain the markedly greater effect of dairy vs. nondairy sources of calcium in modulating adiposity.

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