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White adipose tissue stores energy in the form of lipids, and brown adipose tissue expends energy via uncoupled fatty acid oxidation, which leads to the generation of heat. Obesity reflects an imbalance between energy storage and energy expenditure and is strongly associated with metabolic and cardiovascular disease. Therefore, there are important medical and biological implications for elucidating the mechanisms that promote energy expenditure in humans. Animal models with altered vitamin D receptor (VDR) expression have changes in energy expenditure. However, the specific mechanism for this effect has not been elucidated and the relevance for humans is unclear. Here we show, using human patient samples from individuals with hereditary vitamin D resistant rickets, that the VDR directly inhibits the expression of uncoupling protein-1 (UCP1), the critical protein for uncoupling fatty acid oxidation in brown fat and burning energy. The inhibition is enforced by VDR occupancy of a negative response element in the promoter proximal region of the UCP1 gene. Deletion of VDR increases UCP1 expression and results in a "browning" of adipocytes. Importantly, we found that this process occurs cell autonomously and is independent of the physiologic VDR hormone ligand, 1,25-dihydroxyvitamin D. These results identify a mechanism for modulating energy balance in humans.

Cell-Autonomous Regulation of Brown Fat Identity Gene UCP1 by Unliganded Vitamin D Receptor