Role of uncoupling protein 2 (UCP2) expression and 1alpha, 25-dihydroxyvitamin D3 in modulating adipocyte apoptosis.
We previously found that 1alpha, 25-dihydroxyvitamin D3 [1alpha, 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 1alpha, 25-(OH)2-D3 levels. However, because UCP2 reduces mitochondrial potential, we have evaluated the roles of UCP2, mitochondrial uncoupling, and 1alpha, 25-(OH)2-D3 in adipocyte apoptosis. Overexpressing UCP2 in 3T3-L1 cells induced marked reductions in mitochondrial potential (Deltapsi) 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 1alpha, 25-(OH)2-D3 (0.1-10 nM) restored mitochondrial Deltapsi 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). 1alpha, 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 approximately 50% whereas the high dose increased mitochondrial Ca2+ by 25% (P<0.05); this explains stimulation of apoptosis by the high dose of 1alpha, 25-(OH)2-D3. Using high-calcium diets to suppress 1alpha, 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.
Sun
Xiaocun
X
Department of Nutrition, University of Tennessee, Knoxville, TN 37996-1900, USA.
Zemel
Michael B
MB
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000008:administration & dosage / Q000494:pharmacology; D002454:Cell Differentiation; D005786:Gene Expression Regulation / Q000187:drug effects; D007473:Ion Channels; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D014475:Uncoupling Agents / Q000494:pharmacology; D000071246:Uncoupling Protein 2; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D007473:Ion Channels; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C000604390:Ucp2 protein, mouse; D014475:Uncoupling Agents; D000071246:Uncoupling Protein 2; D051028:bcl-2-Associated X Protein; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D002118:Calcium