title: Impaired histone deacetylases 5 and 6 expression mimics the effects of obesity and hypoxia on adipocyte function.
abstract: The goal of the study was to investigate the role of histone deacetylases (HDACs) in adipocyte function associated with obesity and hypoxia.
  
  
  
  Total proteins and RNA were prepared from human visceral adipose tissues (VAT) of human obese and normal weight subjects and from white adipose tissue (WAT) of C57Bl6-Rj mice fed a normal or high fat diet (HFD) for 16 weeks. HDAC activity was measured by colorimetric assay whereas the gene and protein expression were monitored by real-time PCR and by western blotting, respectively. RNA interference (RNAi) was used to silence the expression of genes in 3T3-L1 adipocytes.
  
  
  
  Total HDAC activity was decreased in VAT and WAT from obese individuals and from mice fed a HFD, respectively. The HDAC activity reduction was associated with decreasedHDAC5/Hdac5andHDAC6/Hdac6expression in human and mice adipocyte fraction. Similarly, hypoxia hampered total Hdac activity and reduced the expression ofHdac5andHdac6in 3T3-L1 adipocytes. The decrease of bothHdac5andHdac6by hypoxia was associated with altered expression of adipokines and of the inducible cAMP early repressor (Icer), a key repressor that is defective in human and mice obesity. Silencing of Icer in adipocytes reproduced the changes in adipokine levels under hypoxia and obesity, suggesting a causative effect. Finally, modeling the defect of the two Hdacs in adipocytes by RNAi or selective inhibitors mimicked the effects of hypoxia on the expression ofIcer, leading to impairment of insulin-induced glucose uptake.
  
  
  
  Hdac5 and Hdac6 expression are required for the adequate expression of Icer and adipocyte function. Altered adipose expression of the two Hdacs in obesity by hypoxia may contribute to the development of metabolic abnormalities.
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, F-59000 Lille, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Bricambert
authors.affiliation: Service of Internal Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-1011 Lausanne, Switzerland.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Favre
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, F-59000 Lille, France; Service of Internal Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-1011 Lausanne, Switzerland.
authors.forename: Saška
authors.initials: S
authors.lastname: Brajkovic
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, F-59000 Lille, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Bonnefond
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, F-59000 Lille, France.
authors.forename: Raphael
authors.initials: R
authors.lastname: Boutry
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, F-59000 Lille, France.
authors.forename: Roberto
authors.initials: R
authors.lastname: Salvi
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, F-59000 Lille, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Plaisance
authors.affiliation: Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, P.O. Box 5825, Doha, Qatar; Univ. Sidi Mohammed Ben Abdellah, FMPF, Fes, Morocco.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Chikri
authors.affiliation: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, F-59000 Lille, France; Inserm, U 1081, Institute for Research on Cancer and Aging of Nice (IRCAN), University of Nice-Sophia Antipolis, Nice and Clinical Chemistry Laboratory, University Hospital, Nice, France.
authors.forename: Giulia
authors.initials: G
authors.lastname: Chinetti-Gbaguidi
authors.affiliation: Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011 - EGID, F-59000 Lille, France.
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.affiliation: Metabolic Center, Fribourg Hospital HFR, Fribourg, Switzerland.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Giusti
authors.affiliation: Univ. Lille, Inserm, CHU Lille, U1190 - EGID, F-59000 Lille, France.
authors.forename: Robert
authors.initials: R
authors.lastname: Caiazzo
authors.affiliation: Univ. Lille, Inserm, CHU Lille, U1190 - EGID, F-59000 Lille, France.
authors.forename: François
authors.initials: F
authors.lastname: Pattou
authors.affiliation: Service of Internal Medicine, Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-1011 Lausanne, Switzerland.
authors.forename: Gérard
authors.initials: G
authors.lastname: Waeber
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, F-59000 Lille, France; Department of Genomic of Common Disease, Imperial College London, UK.
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.affiliation: Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8199 - EGID, F-59000 Lille, France; Department of Genomic of Common Disease, Imperial College London, UK. Electronic address: amar.abderrahmani@univ-lille2.fr.
authors.forename: Amar
authors.initials: A
authors.lastname: Abderrahmani
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D052436:Adipose Tissue, White / Q000166:cytology / Q000201:enzymology; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015687:Cell Hypoxia / Q000502:physiology; D051786:Cyclic AMP Response Element Modulator / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat; D005260:Female; D000073864:Histone Deacetylase 6 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D050152:Intra-Abdominal Fat / Q000166:cytology / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: C497410:CREM protein, human; C497411:Crem protein, mouse; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D051786:Cyclic AMP Response Element Modulator; C012589:trichostatin A; C404500:HDAC5 protein, human; C433811:HDAC6 protein, human; C498618:Hdac5 protein, mouse; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: Adipocytes; Adipokines; Histone deacetylases; Insulin resistance; Obesity