1α,25-dihydroxyvitamin D3 inhibits uncoupling protein 2 expression in human adipocytes

We recently demonstrated that suppressing 1alpha,25-(OH)(2)-D-3 by increasing dietary calcium decreases adipocyte intracellular Ca2+ ([Ca2+](i)), stimulates lipolysis, and inhibits lipogenesis. High calcium diets also increase core temperature and white adipose tissue uncoupling protein 2 (UCP2) expression in aP2-agouti transgenic mice. Accordingly, we have evaluated the role of 1alpha,25-(OH)(2)-D-3 in regulating human adipocyte UCP2 expression. Treatment of human adipocytes for 48 h with 1 nM 1alpha,25-(OH)(2)-D-3 inhibited UCP2 mRNA and protein levels by 50% (P<0.002) and completely blocked isoproterenol- or fatty acid-stimulated two- to threefold increases in UCP2 expression. However, a specific agonist for the membrane vitamin D receptor (mVDR), 1 alpha,25-dihydroxylumisterol(3), was unable to inhibit basal, isoproterenol-stimulated, or fatty acid-stimulated UCP2 expression, whereas a specific mVDR antagonist, 1 beta,25-dihydroxyvitamin D-3, was unable to prevent the 1 alpha,25-(OH)(2)-D-3 inhibition of UCP2 expression. In contrast, nuclear vitamin D receptor (nVDR) knockout via antisense oligodeoxynucleotide (ODN) prevented the inhibitory effect of 1 alpha,25-(OH)(2)-D-3 on adipocyte UCP2 expression and protein levels. These data indicate that 1 alpha,25-(OH)2-D3 exerts an inhibitory effect on adipocyte UCP2 expression via the nVDR. Thus, suppression of 1 alpha,25-(OH)(2)-D-3 and consequent up-regulation of UCP2 may contribute to our previous observation of increased thermogenesis in mice fed with high calcium diets.