1α, 25-dihydroxyvitamin D and corticosteroid regulate adipocyte nuclear vitamin D receptor

Objective: We previously demonstrated that high calcium diets inhibit obesity in both mice and humans; this effect is mediated, in part, by dietary calcium suppression of 1 alpha, 25-dihydroxyvitamin D, which exerts both non-genomic and genomic effects on adipocyte metabolism. However, the presence of the nuclear vitamin D receptor (nVDR) and its role in this regulation in adipocytes have not been investigated. Methods and results: The nVDR is expressed at low levels in preadipocytes, and differentiation induced a rapid 1150% increase within 3 h (P < 0.001), which then declined rapidly to preadipocyte levels at differentiation day 3. However, this was not a differentiation event, as the components of the differentiation mixture (isobutylmethylxanthine and dexamethasone) also increased nVDR expression markedly by 1620 and 284%, respectively, in fully differentiated adipocytes (P < 0.05). 1 alpha, 25-Dihydroxyvitamin D and 11 beta-dehydrocorticosterone each stimulated nVDR expression at 48 h, but not 3 h, by similar to 650% in fully differentiated adipocytes, whereas the combination augmented this effect (P < 0.005). Knockdown of 11 beta-hydroxysteroid dehydrogenase I (11 beta-HSD I) markedly decreased adipocyte nVDR expression and attenuated 1 alpha, 25-dihydroxyvitamin D stimulation of nVDR. Thus, 1 alpha, 25-dihydroxyvitamin D stimulation of corticosteroid synthesis via the 11 beta-HSD appears to provide an indirect positive feedback on the nVDR. 1 alpha, 25-Dihydroxyvitamin D also regulated short-term corticosterone release independently of either 11 beta-HSD I or nVDR. Knockdown 11 beta-HSD I did not affect short-term corticosterone release, whereas modulating calcium influx by KCl, BAYK8644 and the membrane 1 alpha, 25-dihydroxyvitamin D receptor agonist lumisterol markedly increased corticosterone release. Conclusion: These data suggest a potential role of nVDR and corticosterone in the regulation in adipocyte responses to 1 alpha, 25-dihydroxyvitamin D and dietary calcium.