title: Both liver-X receptor (LXR) isoforms control energy expenditure by regulating brown adipose tissue activity.
abstract: 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.
authors.affiliation: Department of Biosciences and Nutrition at NOVUM, Karolinska Institutet, 14183 Huddinge, Sweden. marion.korach-andre@ki.se
authors.forename: Marion
authors.initials: M
authors.lastname: Korach-André
authors.forename: Amena
authors.initials: A
authors.lastname: Archer
authors.forename: Rodrigo P
authors.initials: RP
authors.lastname: Barros
authors.forename: Paolo
authors.initials: P
authors.lastname: Parini
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
mesh_terms: D002001:Adipose Tissue, Brown / Q000378:metabolism* / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D001786:Blood Glucose; D015153:Blotting, Western; D002151:Calorimetry; D004734:Energy Metabolism / Q000502:physiology*; D005260:Female; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007150:Immunohistochemistry; D007473:Ion Channels / Q000378:metabolism*; D000071518:Liver X Receptors; D008279:Magnetic Resonance Imaging; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms / Q000819:agonists / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D022722:Thermogenesis / Q000502:physiology*; D014280:Triglycerides / Q000378:metabolism; D000071256:Uncoupling Protein 1
chemical_list: D001565:Benzoates; D001596:Benzylamines; D001786:Blood Glucose; C473027:GW 3965; D051275:Glucose Transporter Type 4; D007473:Ion Channels; D000071518:Liver X Receptors; D024101:Mitochondrial Proteins; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D020033:Protein Isoforms; C495693:Slc2a4 protein, mouse; D014280:Triglycerides; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1