1,25-Dihydroxyvitamin D₃ Modulation of Adipocyte Glucocorticoid Function

OBJECTIVE: 1,25-Dihydroxyvitamin D₃ dose dependently increases intracellular calcium in human adipocytes. We have demonstrated that suppression of circulating 1,25-dihydroxyvitamin D₃ levels by increasing dietary calcium reduces adipocyte intracellular calcium and reduces adiposity in both humans and rodents, with preferential loss of trunk fat. Autocrine production of cortisol by adipocytes of mice overexpressing 11{szligbeta}-hydroxysteroid dehydrogenase type 1 (11{szligbeta}-HSD 1) in adipose tissue increases visceral adiposity, whereas knockout of 11{szligbeta}-HSD 1 appears to attenuate truncal obesity. Accordingly, our objective was to investigate the role of 1,25-dihydroxyvitamin D₃ in the modulation of adipocyte glucocorticoid metabolism. RESEARCH METHODS AND PROCEDURES: We examined the effect of 1,25-dihydroxyvitamin D₃ or angiotensin II on cortisol production and expression using real-time reverse transcriptase-polymerase chain reaction of 11{szligbeta}-HSD 1, angiotensin II receptor type 1 (AT₁), and AT₂ receptor in human adipocytes. RESULTS: Adipocytes produced negligible cortisol in the absence of substrate (cortisone). In the presence of cortisone (1 to 10 nM), there was significant cortisol production, which was dose dependently augmented (2- to 6-fold, p < 0.001) by 1,25-dihydroxyvitamin D₃ (0.1 to 10 nM). 1,25-Dihydroxyvitamin D₃ dose dependently increased 11{szligbeta}-HSD 1 expression up to 2-fold (p < 0.01) in both the presence and absence of cortisone. In contrast, 1,25-dihydroxyvitamin D₃ dose dependently decreased adipocyte AT₁ expression (by 30% to 50%, p < 0.001) in both the presence and absence of cortisone, suggesting compensatory down-regulation of AT₁. DISCUSSION: We conclude that 1,25-dihydroxyvitamin D₃ directly regulates adipocyte 11{szligbeta}-HSD 1 expression and, consequently, local cortisol levels and that this may contribute to the preferential loss of visceral adiposity by high-calcium diets.