1α,25-dihydroxyvitamin D3 modulates human adipocyte metabolism via nongenomic action

We reported recently that suppression of the renal 1 alpha ,25-dihyroxyvitamin D-3 (1 alpha ,25-(OH)(2)-D-3) production in aP2-agouti transgenic mice by increasing dietary calcium decreases adiposity. However, it was not clear whether this modulation of adipocyte metabolism by dietary calcium is a direct effect of inhibition of 1 alpha ,25-(OH)(2)-D-3-induced [Ca2+]i. Accordingly, we have now evaluated the direct role of 1 alpha ,25-(OH)(2)-D-3. Human adipocytes exhibited a 1 alpha ,25-(OH)(2)-D-3 dose-responsive (1-50 nM) increase in [Ca2+]i (P<0.01). This action was mimicked by 1,25-dihydroxyluministerol(3) (1 alpha ,25-(OH)(2)-lumisterol(3)) (P<0.001), a specific agonist for a putative membrane vitamin D receptor (mVDR), and completely prevented by 1,25-dihydroxyvitamin D-3 (1 beta ,25-(OH)(2)-D-3), a specific antagonist for the mVDR. Similarly, 1 alpha ,25-(OH)(2)-D-3 (5 mM) caused 50%-100% increases in adipocyte fatty acid synthase (FAS) expression and activity (P<0.02), 61% increase in glycerol-3-phosphate dehydrogenase (GPDH) activity (P<0.01), and an 80% inhibition of isoproterenol-stimulated lipolysis (P<0.001), whereas 1,25-(OH)(2)-D-3 completely blocked all these effects. Notably, 1 alpha ,25-OH)(2)-lumisterol(3) exerted more potent effects in modulating adipocyte lipid metabolism, with 2.5- to 3.0-fold increases in FAS expression and activity (P<0.001) and a threefold increase in GPDH activity (P<0.001). Also 1 alpha ,25-(OH)(2)-lumisterol3 was approximately twice as potent in inhibiting basal lipolysis (P<0.025), whereas 1,25-(OH)(2)-D-3 completely blocked all these effects. These data suggest that 1 alpha ,25-(OH)(2)-D-3 modulates adipocyte Ca2+ signaling and, consequently, exerts a coordinated control over lipogenesis and lipolysis. Thus, a direct inhibition of 1 alpha ,25-(OH)(2)-D-3-induced [Ca2+](i) may contribute to an anti-obesity effect of dietary calcium, and the mVDR may represent an important target for obesity.