Both liver-X receptor (LXR) isoforms control energy expenditure by regulating brown adipose tissue activity

Brown adipocytes are multilocular lipid storage cells that play a crucial role in nonshivering thermogenesis. Uncoupling protein 1 (UCP1) is a unique feature of brown fat cells that allows heat generation on sympathetic nervous system stimulation. As conventional transcriptional factors that are activated in various signaling pathways, liver-X receptors (LXRs) play important roles in many physiological processes. The role of LXRs in the regulation of energy homeostasis remains unclear, however. Female WT, LXRαβ^-/-, LXRα^-/-, and LXRβ^-/- mice were fed with either a normal diet (ND) or a high-carbohydrate diet (HCD) supplemented with or without GW3965-LXR agonist. LXRαβ^-/- mice exhibited higher energy expenditure (EE) as well as higher UCP1 expression in brown adipose tissue (BAT) compared with WT mice on the HCD. In addition, long-term treatment of WT mice with GW3965 showed lower EE at thermoneutrality (30 °C) and lower Ucp1 expression level in BAT. Furthermore, H&E staining of the BAT of LXRαβ^-/- mice exhibited decreased lipid droplet size compared with WT mice on the HCD associated with a more intense UCP1-positive reaction. Quantification of triglyceride (TG) content in BAT showed lower TG accumulation in LXRβ^-/- mice compared with WT mice. Surprisingly, GW3965 treatment increased TG content (twofold) in the BAT of WT and LXRα^-/- mice but not in LXRβ^-/- mice. Furthermore, glucose transporter (GLUT4) in the BAT of LXRα^-/- and LXRβ^-/- mice was sixfold and fourfold increased, respectively, compared with WT mice on the ND. These findings suggest that LXRα as well as LXRβ could play a crucial role in the regulation of energy homeostasis in female mice and may be a potential target for the treatment of obesity and energy regulation.