Activation of autophagy and AMPK by gamma-tocotrienol suppresses the adipogenesis in human adipose derived stem cells

ScopeThis study investigated the mechanistic details by which gamma-tocotrienol (-T3) manipulates adipocyte differentiation in human adipose derived stem cells (hASCs). Methods and results-T3 specifically inhibited the early stage of adipocyte differentiation by acting on downstream of C/EBP- but upstream of C/EBP- in hASCs. In searching a potential mechanism, we identified that -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 -T3 induced caspase3-mediated apoptotic cell death. The blockage of AMPK by a dominant negative mutant of AMPK was insufficient to normalize -T3-mediated autophagy, suggesting that enhanced autophagic activity of -T3 is independent of AMPK activation. Intriguingly, AMPK inhibition significantly restored PPAR- activation, but marginally rescued lipid-loaded adipocyte morphology due to, at least partly, a lack of lipid droplet-coating protein. These data suggest that -T3 activates AMPK and autophagy signaling, which synergistically contributes to the suppression of adipogenic conversion of hASCs into adipocytes. ConclusionThese results provide a novel insight into the molecular mechanism involved in anti-adipogenic action of -T3 in humans via AMPK and autophagy activation. Thus, -T3 may constitute a new dietary avenue to attenuate hyperplastic obesity in humans.