Epidemiological evidence suggests that low calcium intakes are associated with weight gain and obesity. However, the mechanism by which calcium may influence body weight in humans is not known. Animal studies are impotent tools to help elucidate possible mechanisms of action of nutrients, because they allow treatments that would be considered unethical in humans. Rat studies have been conducted to determine the mechanism of action of calcium on body weight regulation and results from these studies suggest that the calcium sensing receptor (CaSR) may play an important role in the modulation of the expression of rate limiting lipolytic enzymes in adipocytes. The CaSR is most widely researched for its function in the regulation of extracellular calcium within narrow limits by modulating parathyroid secretion and calcium reabsorption in the kidney. Its role in lipolysis is newly discovered and may help explain the epidemiological evidence associating calcium with weight loss.
Rats fed diets low calcium diets for 15 weeks show increasing visceral fat accumulation, lower serum free fatty acids and glycerol concentrations, and increased expression of CaSR in white adipose tissue, when compared to those fed normal intakes of calcium1. The lower serum free fatty acids and glycerol suggest that decreased adipocyte lipolysis occurs with low calcium intakes. In addition, the low calcium diet rats had lower levels of hormone sensitive lipase and adipose triglyceride lipase protein, but higher levels of fatty acid synthase protein, compared to normal calcium diet rats. Even larger changes from the normal calcium diet rats were seen in a group of rats fed very low calcium diets. These results suggest that low calcium diets cause down regulation of hormone sensitive lipase and adipose triglyceride lipase expression and have antilipolytic effects through reductions in triglyceride breakdown from adipose tissue.
In vitro experiments performed by the same researchers showed that the expression of the CaSR was stimulated by the vitamin D metabolite 1,25-dihydroxyvitamin D, through binding to the nuclear vitamin D receptor. The result of 1,25-dihydroxyvitamin D binding to its nuclear receptor was an increase in intracellular calcium, a decrease in intracellular cAMP, and a down regulation of hormone sensitive lipase and adipose triglyceride lipase protein expression, which resulted in an antilipolytic effect. Small interfering RNA for the nuclear vitamin D receptor or the CaSR decreased this antilipolytic effect, but application of calcium or parathyroid hormone to the extracellular fluid did not, suggesting that CaSR expression in adipocytes in regulated by 1,25-dihydroxyvitamin D rather than extracellular calcium. Previous research has shown that 1,25-dihydroxyvitamin D regulates CaSR expression in adipocytes. Low calcium levels may therefore raise 1,25-dihydroxyvitamin D levels, which ultimately increase intracellular calcium and decrease lipolysis.
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