Mechanisms calcium and the regulation of energy metabolism

How does calcium work? Although the physiological or cell-biology basis for the changes in body weight and body fat has not been fully elucidated, a hypothesis has been developed by Zemel and co-workers (2000), based largely on experiments in the obese agouti mutant mouse (Jones et al., 1996, Shi et al., 2001, Xue et al., 1998, 2001, Zemel et al., 1995). The agouti protein is involved in the development of the wild-type coat colour of agoutis (South-American guinea pig-like rodents), mice and other mammals. Furthermore, it plays a role in the regulation of food intake. Overexpression of this protein due to a vital mutation in the encoding gene locus in mice not only leads to a yellowish coat colour, but also to body fat accumulation, insulin resistance and hyperinsulinaemia with aging. Feeding highly palatable diets to these animals causes overeating and leads to obesity, an effect that can be prevented by increasing the calcium content of the diets, e.g. from 0.4 to 1.2% (Zemel et al., 2000).

According to Zemel's hypothesis, consumption of relatively large amounts of dietary calcium increases circulating [Ca2+] and decreases counter-regulatory serum concentrations of the calcitropic hormones PTH and, as a consequence, vitamin D (calcitriol, 1,25-dihydroxy-vitamin D3). Calcitriol increases intracellular [Ca2+] in cultured human adipocytes when added to the cell-culture medium. This means for the above-mentioned metabolic steps, that the decreased serum calcitriol in turn down-regulates Ca2+ influx into adipocytes and thereby reduces intracellular [Ca2+] (Fujita and Palmieri, 2000, Palmieri et al., 1998, Shi et al., 2001, Zemel et al., 2000). Intracellular calcium is involved in the regulation of several key enzymes of fat and energy metabolism, including fatty acid synthase. Decreased adipocyte intracellular [Ca2+] thereby stimulates lipolysis, fatty acid oxidation (Melanson et al., 2003) and in some studies the expression of uncoupling protein 2 and thereby thermogenesis. According to these mechanisms, increased body core temperature was observed in mice fed a high-calcium diet (Zemel et al., 2000). At the same time lipogenic gene expression and fatty acid synthase activity are inhibited, but a contribution of de novo lipogenesis in the development of obesity in humans remains doubtful (Hellerstein, 1999). All these effects result in decreased adipocyte lipid accumulation (Shi et al., 2001), weight and body fat reduction and an overall shift of dietary energy from adipose tissue to lean body mass.

Other studies, however, did not support these proposed mechanisms. Feeding normal or energy-dense diets differing in calcium content (0.21.8%) to normal and obese rats and mice had no significant effect on energy intake, body weight and body fat, and did not show the inverse relationship between 1,25-dihydroxy-vitamin D3 or PTH and body weight (Paradis and Cabanac, 2005, Zhang and Tordoff, 2004). Papakonstantinou and co-workers (2003) observed less weight gain and less body fat in rats on a high- (2.4%) compared with a low- (0.4%) calcium diet. They, however, did not find the increase in body core temperature as predicted by Zemel, and the observed effects on fat and weight were explained simply by increased faecal excretion of fat.

This brings up again an idea proposed a longer time ago, according to which the divalent cation calcium prevents the intestinal absorption of part of the dietary fat and increases faecal lipid loss and sterol excretion forming insoluble fatty acid soaps and bile salts (Denke et al., 1993, Drenick, 1961, Vaskonen et al., 2001, 2002, Vaskonen 2003, Welberg et al., 1994). By the same mechanism calcium may enhance a cholesterol-lowering effect of other food components, e.g. plant sterols (Vaskonen et al., 2001). The extent of this effect increased with an increasing proportion of long-chain saturated fatty acids in the diet, whereby, with Western eating habits, the energy excretion with fat is probably around 1 and 3% of the daily energy supply, i.e. around 30 and 90 kcal/day. In a study by Shahkhalalili and co-workers (2001) calcium fortification of chocolate doubled calcium ingestion from 950 to 1855 mg/day and increased faecal fat excretion by ~36 kcal/day (4.04 g/day). This effect seems small, but in the long run it can contribute a significant share to fat and weight loss. From the above data a body-fat reduction by 1-4 kg/year is calculated, although other studies find weaker effects (Table 11.2).

Table 11.2 Effect of a 300 mg (one serving) increment in regular calcium intake on body weight and body fat (according to Heaney et al. (2002))

Group Period ABody weight* ABody fat* Reference


Young women

Middle-aged women Elderly women

Adult women

African-American men

2-96 month 8 years 1 year 1 year n.a. 1 year

Carruth and

Skinner, 2001 Davies et al., 2000 Davies et al., 2000 D avies et al., 2000 Zemel et al., 2000 Zemel et al., 1990

* Differences between groups or highest versus lowest quartiles in cross-sectional studies, or differences per year in longitudinal and intervention studies.

A third possible mechanism, which may slightly contribute to weight reduction as well, has been the subject of a recent publication (Ping-Delfos et al., 2004). In a randomised, blind, controlled cross-over study with a sequential-meal design, 11 overweight or obese subjects (mean BMI 31 kg/ m2) consumed isocaloric high (543 mg calcium and 349 IU vitamin D) and low (248 mg calcium and 12 IU vitamin D) dairy calcium breakfasts followed by a very low calcium (48 mg calcium and 25 IU vitamin D) standard lunch. High calcium intake did not affect hunger and satiety immediately after the meal, but did significantly reduce spontaneous food intake over the subsequent 24 h.

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