title: Activation of autophagy and AMPK by gamma-tocotrienol suppresses the adipogenesis in human adipose derived stem cells.
abstract: METHODS
  This study investigated the mechanistic details by which gamma-tocotrienol (γ-T3) manipulates adipocyte differentiation in human adipose derived stem cells (hASCs).
  
  
  RESULTS
  γ-T3 specifically inhibited the early stage of adipocyte differentiation by acting on downstream of C/EBP-β but upstream of C/EBP-α in hASCs. In searching a potential mechanism, we identified that γ-T3 promoted two catabolic signaling pathways: (i) AMP kinase (AMPK), and (ii) enhanced autophagy, as assessed by autophagic flux and cytosolic autophagosome (LC3II) accumulation. In addition, chronic exposure of γ-T3 induced caspase3-mediated apoptotic cell death. The blockage of AMPK by a dominant negative mutant of AMPK was insufficient to normalize γ-T3-mediated autophagy, suggesting that enhanced autophagic activity of γ-T3 is independent of AMPK activation. Intriguingly, AMPK inhibition significantly restored PPAR-γ activation, but marginally rescued lipid-loaded adipocyte morphology due to, at least partly, a lack of lipid droplet-coating protein. These data suggest that γ-T3 activates AMPK and autophagy signaling, which synergistically contributes to the suppression of adipogenic conversion of hASCs into adipocytes.
  
  
  CONCLUSIONS
  These results provide a novel insight into the molecular mechanism involved in anti-adipogenic action of γ-T3 in humans via AMPK and autophagy activation. Thus, γ-T3 may constitute a new dietary avenue to attenuate hyperplastic obesity in humans.
authors.affiliation: Department of Food Science and Human Nutrition, University of Florida, Gainesville, FL, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhao
authors.forename: Jung-Heun
authors.initials: JH
authors.lastname: Ha
authors.forename: Meshail
authors.initials: M
authors.lastname: Okla
authors.forename: Soonkyu
authors.initials: S
authors.lastname: Chung
mesh_terms: D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism*; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects; D000273:Adipose Tissue / Q000166:cytology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D047495:PPAR gamma / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D002839:Chromans; D047495:PPAR gamma; D014810:Vitamin E; C013649:plastochromanol 8; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000263:Adenylate Kinase
keywords: AMP kinase; Adipogenesis; Autophagy; Gamma-tocotrienol; Obesity