title: LXR is a negative regulator of glucose uptake in human adipocytes.
abstract: OBJECTIVE
  Obesity increases the risk of developing type 2 diabetes mellitus, characterised by impaired insulin-mediated glucose uptake in peripheral tissues. Liver X receptor (LXR) is a positive regulator of adipocyte glucose transport in murine models and a possible target for diabetes treatment. However, the levels of LXRα are increased in obese adipose tissue in humans. We aimed to investigate the transcriptome of LXR and the role of LXR in the regulation of glucose uptake in primary human adipocytes.
  
  
  METHODS
  The insulin responsiveness of human adipocytes differentiated in vitro was characterised, adipocytes were treated with the LXR agonist GW3965 and global transcriptome profiling was determined by microarray, followed by quantitative RT-PCR (qRT-PCR), western blot and ELISA. Basal and insulin-stimulated glucose uptake was measured and the effect on plasma membrane translocation of glucose transporter 4 (GLUT4) was assayed.
  
  
  RESULTS
  LXR activation resulted in transcriptional suppression of several insulin signalling genes, such as AKT2, SORBS1 and CAV1, but caused only minor changes (<15%) in microRNA expression. Activation of LXR impaired the plasma membrane translocation of GLUT4, but not the expression of its gene, SLC2A4. LXR activation also diminished insulin-stimulated glucose transport and lipogenesis in adipocytes obtained from overweight individuals. Furthermore, AKT2 expression was reduced in obese adipose tissue, and AKT2 and SORBS1 expression was inversely correlated with BMI and HOMA index.
  
  
  CONCLUSIONS
  In contrast to murine models, LXR downregulates insulin-stimulated glucose uptake in human adipocytes from overweight individuals. This could be due to suppression of Akt2, c-Cbl-associated protein and caveolin-1. These findings challenge the idea of LXR as a drug target in the treatment of diabetes.
authors.affiliation: Department of Medicine Huddinge, Karolinska Institutet, Hälsovägen 7, Novum, 14186 Stockholm, Sweden. annie.pettersson@ki.se
authors.forename: A M L
authors.initials: AM
authors.lastname: Pettersson
authors.forename: B M
authors.initials: BM
authors.lastname: Stenson
authors.forename: S
authors.initials: S
authors.lastname: Lorente-Cebrián
authors.forename: D P
authors.initials: DP
authors.lastname: Andersson
authors.forename: N
authors.initials: N
authors.lastname: Mejhert
authors.forename: J
authors.initials: J
authors.lastname: Krätzel
authors.forename: G
authors.initials: G
authors.lastname: Aström
authors.forename: I
authors.initials: I
authors.lastname: Dahlman
authors.forename: A V
authors.initials: AV
authors.lastname: Chibalin
authors.forename: P
authors.initials: P
authors.lastname: Arner
authors.forename: J
authors.initials: J
authors.lastname: Laurencikiene
mesh_terms: D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005947:Glucose / Q000378:metabolism; D006801:Humans; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D001565:Benzoates; D001596:Benzylamines; C473027:GW 3965; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D005947:Glucose