1,25-Dihydroxyvitamin D3/vitamin D receptor suppresses brown adipocyte differentiation and mitochondrial respiration

The vitamin D system plays a role in metabolism regulation. 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) suppressed 3T3-L1 white adipocyte differentiation. Vitamin D receptor (VDR) knockout mice showed increased energy expenditure, whereas mice with adipose-specific VDR over-expression showed decreased energy expenditure. Brown adipose tissue (BAT), now known to be present in adult humans, functions in non-shivering thermogenesis by uncoupling ATP synthesis from respiration and plays an important role in energy expenditure. However, the effects of 1,25(OH)(2)D-3/VDR on brown adipocyte differentiation and mitochondrial respiration have not been reported. mRNA expression of VDR and the metabolizing enzymes 1 alpha-hydroxylase (CYP27B1) and 24-hydroxylase (CYP24A1) were examined in BAT of mice models of obesity and during brown adipocyte differentiation. The effects of 1,25(OH)(2)D-3 and VDR over-expression on brown adipocyte differentiation and functional outcomes were evaluated. No significant changes in mRNA of VDR and CYP27B1 were noted in both diet-induced obese (DIO) and ob/ob mice, whereas uncoupling protein 1 mRNA was downregulated in BAT of ob/ob, but not DIO mice when compared to the controls. In contrast, mRNA of VDR, CYP24A1, and CYP27B1 were downregulated during brown adipocyte differentiation in vitro. 1,25(OH)(2)D-3 dose-dependently suppressed brown adipocyte differentiation, accompanied by suppressed isoproterenol-stimulated oxygen consumption rates (OCR), maximal OCR and OCR from proton leak. Consistently, over-expression of VDR also suppressed brown adipocyte differentiation. Further, both 1,25(OH)(2)D-3 and VDR over-expression suppressed PPAR gamma transactivation in brown preadipocytes. Our results demonstrate the suppressive effects of 1,25(OH)(2)D-3/VDR signaling on brown adipocyte differentiation and mitochondrial respiration. The role of 1,25(OH)(2)D-3/VDR system in regulating BAT development and function in obesity warrant further investigation.