title: Is oxygen a key factor in the lipodystrophy phenotype?
abstract: BACKGROUND
  The lipodystrophic syndrome (LD) is a disorder resulting from selective damage of adipose tissue by antiretroviral drugs included in therapy controlling human-immunodeficiency-virus-1. In the therapy cocktail the nucleoside reverse transcriptase inhibitors (NRTI) contribute to the development of this syndrome. Cellular target of NRTI was identified as the mitochondrial polymerase-gamma and their toxicity described as a mitochondrial DNA (mtDNA) depletion resulting in a mitochondrial cytopathy and involved in fat redistribution. No mechanisms offer explanation whatsoever for the lipo-atrophic and lipo-hypertrophic phenotype of LD. To understand the occurrence we proposed that the pO2 (oxygen partial pressure) could be a key factor in the development of the LD. For the first time, we report here differential effects of NRTIs on human adipose cells depending on pO2 conditions.
  
  
  CONCLUSIONS
  We showed that the hypoxia conditions could alter adipogenesis process by modifying expression of adipocyte makers as leptin and the peroxisome proliferator-activated receptor PPARgamma and inhibiting triglyceride (TG) accumulation in adipocytes. Toxicity of NRTI followed on adipose cells in culture under normoxia versus hypoxia conditions showed, differential effects of drugs on mtDNA of these cells depending on pO2 conditions. Moreover, NRTI-treated adipocytes were refractory to the inhibition of adipogenesis under hypoxia. Finally, our hypothesis that variations of pO2 could exist between adipose tissue from anatomical origins was supported by staining of the hypoxic-induced angiopoietin ANGPTL4 depended on the location of fat.
  
  
  CONCLUSIONS
  Toxicity of NRTIs have been shown to be opposite on human adipose cells depending on the oxygen availability. These data suggest that the LD phenotype may be a differential consequence of NRTI effects, depending on the metabolic status of the targeted adipose tissues and provide new insights into the opposite effects of antiretroviral treatment, as observed for the lipo-atrophic and lipo-hypertrophic phenotype characteristic of LD.
authors.affiliation: Institut Cochin UMR 8104 Inserm U567 Université René Descartes 22 rue Méchain, 75014 Paris, France. gentil@genethon.fr
authors.forename: Christel
authors.initials: C
authors.lastname: Gentil
authors.forename: Sébastien
authors.initials: S
authors.lastname: Le Jan
authors.forename: Josette
authors.initials: J
authors.lastname: Philippe
authors.forename: Jacques
authors.initials: J
authors.lastname: Leibowitch
authors.forename: Pierre
authors.initials: P
authors.lastname: Sonigo
authors.forename: Stéphane
authors.initials: S
authors.lastname: Germain
authors.forename: France
authors.initials: F
authors.lastname: Piétri-Rouxel
mesh_terms: D050156:Adipogenesis / Q000187:drug effects / Q000502:physiology; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000187:drug effects; D005786:Gene Expression Regulation; D039682:HIV-Associated Lipodystrophy Syndrome / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D020738:Leptin / Q000235:genetics / Q000378:metabolism; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D010456:Peptides, Cyclic; D010641:Phenotype; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects*; D013004:Somatostatin / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000235:genetics / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D020738:Leptin; D009842:Oligopeptides; D047495:PPAR gamma; D010456:Peptides, Cyclic; D018894:Reverse Transcriptase Inhibitors; D014280:Triglycerides; C060347:lanreotide; D013004:Somatostatin; D010100:Oxygen