Liver X receptor α is a transcriptional repressor of the uncoupling protein 1 gene and the brown fat phenotype

The adipocyte integrates crucial information about metabolic needs in order to balance energy intake, storage, and expenditure. Whereas white adipose tissue stores energy, brown adipose tissue is a major site of energy dissipation through adaptive thermogenesis mediated by uncoupling protein 1 (UCP1) in mammals. In both white and brown adipose tissue, nuclear receptors and their coregulators, such as peroxisome proliferator-activated receptor gamma (PPAR gamma) and PPAR gamma coactivator 1 alpha (PGC-1 alpha), play key roles in regulating their development and metabolic functions. Here we show the unexpected role of liver X receptor alpha (LXR alpha) as a direct transcriptional inhibitor of beta-adrenergic receptor-mediated, cyclic AMP-dependent Ucp1 gene expression through its binding to the critical enhancer region of the Ucp1 promoter. The mechanism of inhibition involves the differential recruitment of the corepressor RIP140 to an LXR alpha binding site that overlaps with the PPAR gamma/PGC-1 alpha response element, resulting in the dismissal of PPAR gamma. The ability of LXR alpha to dampen energy expenditure in this way provides another mechanism for maintaining a balance between energy storage and utilization.