Modulation of apoptosis is emerging as a promising antiobesity strategy because removal of adipocytes through this process will result in reducing body fat. Effects of vitamin D on apoptosis are mediated via multiple signaling pathways that involve common regulators and effectors converging on cellular Ca²⁺. We have previously shown that 1,25‐dihydroxyvitamin D₃ induces the Ca²⁺ signal associated with activation of Ca²⁺‐dependent apoptotic proteases in mature adipocytes. In this study, a diet‐induced obesity (DIO) mouse model was used to evaluate the role of vitamin D and calcium in adiposity.

DIO mice fed high vitamin D₃, high Ca, and high D₃ plus high Ca diets demonstrated a decreased body and fat weight gain, improved markers of adiposity and vitamin D status (plasma concentrations of glucose, insulin, adiponectin, 25‐hydroxyvitamin D, 1,25‐dihydroxyvitamin D, parathyroid hormone (PTH)), but an increased plasma Ca²⁺. High D₃ and Ca intakes were associated with induction of apoptosis and activation of Ca²⁺‐dependent apoptotic proteases, calpain and caspase‐12, in adipose tissue of DIO mice. The combination of D₃ plus Ca was more effective than D₃ or Ca alone in decreasing adiposity.

The results imply that high vitamin D and Ca intakes activate the Ca²⁺‐mediated apoptotic pathway in adipose tissue. Targeting this pathway with vitamin D and Ca supplementation could contribute to the prevention and treatment of obesity. However, this potentially effective and affordable approach needs to be evaluated from a safety point of view.