title: Phosphorylation of GATA2 by Akt increases adipose tissue differentiation and reduces adipose tissue-related inflammation: a novel pathway linking obesity to atherosclerosis.
abstract: BACKGROUND
  Obesity-related inflammation is emerging as a major cause of insulin resistance and cardiovascular diseases. GATA2 transcription factor is an inhibitor of adipogenesis and an activator of vascular cells. We hypothesized that GATA2 activity is controlled by insulin during adipogenesis, linking metabolic homeostasis and inflammation.
  
  
  RESULTS
  We show that insulin induces GATA2 phosphorylation on serine 401 in a PI-3K/Akt-dependent manner. Insulin-dependent phosphorylation of serine 401 impairs GATA2 translocation to the nucleus and its DNA binding activity. A GATA2 mutant not phosphorylable by Akt (GATA2(S401A)) acts similarly to wild-type GATA2. In contrast, a GATA2 mutant that mimics Akt phosphorylation (GATA2(S401D)) is restrained in the cytoplasm. Cultured preadipocytes bearing GATA2(S401A) do not convert to adipocytes and express high levels of inflammatory cytokines like monocyte chemotactic protein-1 (MCP-1). On the contrary, GATA2(S401D) preadipocytes differentiate to adipocytes. When GATA2(S401A) preadipocytes are injected in mice fed a high-fat diet, they do not differentiate adequately into adipocytes, maintaining the expression of inflammatory markers like MCP-1. In contrast, injection of GATA2(S401D) preadipocytes in mice fed a high-fat diet results in development of adipocytes and no expression of inflammatory markers.
  
  
  CONCLUSIONS
  GATA2 could be a new target in the prevention and treatment of obesity-related inflammation and its complications.
authors.affiliation: Department of Internal Medicine, University of Rome Tor Vergata, Policlinico Tor Vergata-PTV University Hospital, Rome, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Menghini
authors.forename: Valentina
authors.initials: V
authors.lastname: Marchetti
authors.forename: Marina
authors.initials: M
authors.lastname: Cardellini
authors.forename: Marta L
authors.initials: ML
authors.lastname: Hribal
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mauriello
authors.forename: Davide
authors.initials: D
authors.lastname: Lauro
authors.forename: Paolo
authors.initials: P
authors.lastname: Sbraccia
authors.forename: Renato
authors.initials: R
authors.lastname: Lauro
authors.forename: Massimo
authors.initials: M
authors.lastname: Federici
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000273:Adipose Tissue / Q000166:cytology* / Q000473:pathology; D001161:Arteriosclerosis / Q000209:etiology; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D050989:GATA2 Transcription Factor; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D007328:Insulin / Q000494:pharmacology; D009765:Obesity / Q000150:complications; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000502:physiology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D050989:GATA2 Transcription Factor; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; C494711:GATA2 protein, human; C494918:AKT1 protein, human