Recent data from this laboratory demonstrate that increasing adipocyte intracellular Ca(2+) results in a coordinated stimulation of lipogenesis and inhibition of lipolysis. We have also noted that increasing dietary calcium of obese patients for 1 year resulted in a 4.9 kg loss of body fat (P<0.01). Accordingly, we tested the possibility that calcitrophic hormones may act on adipocytes to increase Ca(2+) and lipid metabolism by measuring the effects of 1, 25-(OH)(2)-D in primary cultures of human adipocytes, and found significant, sustained increases in intracellular Ca(2+) and a corresponding marked inhibition of lipolysis (EC(50) approximately 50 pM; P<0.001), suggesting that dietary calcium could reduce adipocyte mass by suppressing 1,25-(OH)(2)-D. To test this hypothesis, we placed transgenic mice expressing the agouti gene specifically in adipocytes on a low (0.4%) Ca/high fat/high sucrose diet either unsupplemented or with 25 or 50% of the protein replaced by non-fat dry milk or supplemented to 1.2% Ca with CaCO(3) for 6 wk. Weight gain and fat pad mass were reduced by 26-39% by the three high calcium diets (P<0.001). The high calcium diets exerted a corresponding 51% inhibition of adipocyte fatty acid synthase expression and activity (P<0.002) and stimulation of lipolysis by 3. 4- to 5.2-fold (P<0.015). This concept of calcium modulation of adiposity was further evaluated epidemiologically in the NHANES III data set. After controlling for energy intake, relative risk of being in the highest quartile of body fat was set to 1.00 for the lowest quartile of Ca intake and was reduced to 0.75, 0.40, and 0.16 for the second, third, and fourth quartiles, respectively, of calcium intake for women (n=380;P<0.0009); a similar inverse relationship was also noted in men (n=7114; P<0.0006). Thus, increasing dietary calcium suppresses adipocyte intracellular Ca(2+) and thereby modulates energy metabolism and attenuates obesity risk.

We have demonstrated previously a regulatory role for intracellular Ca2+ ([Ca2+]i) in adipocyte lipogenesis and lipolysis and have recently reported that 1,25-(OH)2-D increases adipocyte [Ca2+]i, which causes increased lipogenesis and decreased lipolysis. We have now tested the hypothesis that suppressing 1,25-(OH)2-D by increasing dietary calcium will suppress adipocyte [Ca2+]i, thereby facilitating weight loss by stimulating lipolysis and inhibiting lipogenesis in calorically (Kcal)-restricted (70% of ad lib) aP2-agouti transgenic (aP2-a) mice. Mice (aP2-a) exhibiting a pattern of obesity gene expression similar to humans were fed a low-Ca (0.4%)/high-fat/high-sucrose diet for six weeks, resulting in a 27% and twofold increase in body weight and total fat pad mass, respectively, with a twofold increase in adipocyte [Ca2+]i pad lib or Kcal-restricted (70% of ad lib) on this diet either unsupplemented (basal) or with 25% or 50% of the protein replaced by non-fat dry milk (medium or high) dairy or supplemented with CaCO3 to 1.2% Ca for six weeks. Adipocyte [Ca2+]i was unaffected by Kcal restriction but was reduced markedly by all three high Ca diets (290 vs. 130 nM, p2+]i and thereby reduce energy storage and increase thermogenesis during Kcal restriction.

A large body of scientific evidence collected in recent decades demonstrates that an adequate intake of calcium and other nutrients from dairy foods reduces the risk of osteoporosis by increasing bone acquisition during growth, slowing age-related bone loss, and reducing osteoporotic fractures. These results have culminated in the new (2005) Dietary Guidelines for Americans that now recommend 3 servings of milk products per day to reduce the risk of low bone mass and contribute important amounts of many nutrients that may have additional health attributes beyond bone health. A number of animal, observational, and clinical studies have shown that dairy food consumption can help reduce the risk of hypertension. Clinical trials indicate that the consumption of recommended levels of dairy products, as part of a healthy diet, can contribute to lower blood pressure in individuals with normal and elevated blood pressure. Emerging data also indicate that specific peptides associated with casein and whey proteins can significantly lower blood pressure. In addition, a growing body of evidence has provided support for a beneficial effect of dairy foods on body weight and fat loss. Clinical studies have demonstrated that during caloric restriction, body weight and body fat loss occurs when adequate calcium is provided by supplements and that this effect is further augmented by an equivalent amount of calcium supplied from dairy foods. Several studies support a role for calcium, vitamin D, and dairy foods against colon cancer. Additionally, conjugated linoleic acid, a fatty acid found naturally in dairy fat, confers a wide range of anticarcinogenic benefits in experimental animal models and is especially consistent for protection against breast cancer.

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The aim of the present study was to examine the effects of oral supplementation of newborn Balb/c mice with bifidobacteria (B. infantis, B. bifidum) and iron-free apo-lactoferrin (bovine, human) on gut endotoxin concentration and mucosal immunity. Endotoxin concentration was measured in ileocecal filtrates at 7, 14, 21, and 28 days postdelivery by a quantitative limulus amebocyte lysate test. While endotoxin levels in bifidobacteria-fed mice showed a steady rise over time, they were consistently lower than that observed in control animals. Results of lactoferrin supplementation varied depending on the specific time point, but overall by day 28, all treatment groups showed lower intestinal endotoxin concentrations compared to saline fed animals. Neither bifidobacteria nor lactoferrin stimulated an increase in B or T cells, or in cytokine production (IL-6, TNF-alpha, INF-gamma), in Peyer's patches as measured by flow cytometry. Bifidobacteria and lactoferrin were well tolerated as dietary supplements and showed promising potential to reduce gut endotoxin levels.