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E-mail contact: mzemel{at}utk.edu
We previously found that 1α, 25-dihydroxyvitamin D3 [1α, 25-(OH)2-D3] modulates adipocyte lipid metabolism via a Ca2+-dependent mechanism and inhibits adipocyte UCP2 expression, indicating that the anti-obesity effects of dietary calcium are mediated by suppression of 1α, 25-(OH)2-D3 levels. However, because UCP2 reduces mitochondrial potential, we have evaluated the roles of UCP2, mitochondrial uncoupling, and 1α, 25-(OH)2-D3 in adipocyte apoptosis. Overexpressing UCP2 in 3T3-L1 cells induced marked reductions in mitochondrial potential (Δψ) and ATP production (P<0.01), increases in the expression of caspases (P<0.05), and a decrease in Bcl-2/Bax expression ratio (P<0.01). Physiological doses of 1α, 25-(OH)2-D3 (0.1–10 nM) restored mitochondrial Δψ in LI-UCP2 cells and protected against UCP2 overexpression-induced apoptosis (P<0.01), whereas a high dose (100 nM) stimulated apoptosis in 3T3-L1 and L1-UCP2 cells (P<0.05). 1α, 25-(OH)2-D3 stimulated cytosolic Ca2+ dose-dependently in both 3T3-L1 and L1-UCP2 cells. However, physiological doses suppressed mitochondrial Ca2+ levels by ~50% whereas the high dose increased mitochondrial Ca2+ by 25% (P<0.05); this explains stimulation of apoptosis by the high dose of 1α, 25-(OH)2-D3. Using high-calcium diets to suppress 1α, 25-(OH)2-D3 stimulated adipose tissue apoptosis in aP2 transgenic mice (P<0.01), suggesting that increasing dietary calcium stimulates adipose apoptosis and thereby further contributes to an anti-obesity effect of dietary calcium.
Key words: calcitriol • calcium • mitochondrial potential • obesity
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