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

Abstract

Scope: This study investigated the mechanistic details by which gamma-tocotrienol (γ-T3) manipulates adipocyte differentiation in human adipose derived stem cells (hASCs). Methods and 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 lipidloaded 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. Conclusion: 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-T3may constitute a new dietary avenue to attenuate hyperplastic obesity in humans.

Muscadine grape seed oil as a novel source of tocotrienols to reduce adipogenesis and adipocyte inflammation

“…Moreover, the results indicate that dioxane/hexane may be the better method to extract the TRF, because the major T3s eluted (e.g., γT3 and δT3) have been demonstrated to be more effective at inhibiting adipogenesis than αT3. 11 In this study, MGSO was able to reduce the mRNA expression of two major transcription factors of adipogenesis, i.e., PPARγ and CEBPα, and to decrease the mRNA and protein expression of the downstream targets of adipogenesis ( Fig. 3B and 4).…”

“…10 Moreover, it was recently demonstrated that pure γT3 at a concentration as low as 1 μM was able to inhibit new fat cell formation (adipogenesis) in human adipogenic precursor cells. 11 Thus far, the evidence gained by our group and others strongly suggests that γT3 may be used as a promising dietary strategy to prevent hyperplastic obesity.…”

Suppression of NLRP3 inflammasome by γ-tocotrienol ameliorates type 2 diabetes

“…Our previous work as well as others has shown that ␥ T3 can block NF B activation ( 5-7 ) and stimulate AMPactivated protein kinase (AMPK) and autophagy in a variety of cell types (15)(16)(17)(18). In the present study, we ask whether ␥ T3 represses the NLRP3 infl ammasome and associated infl ammatory processes in type 2 diabetes by modulating NF B, AMPK, and autophagy signaling pathways.…”

“…Gene expression analysis was performed as described previously ( 18 ). Relative gene expression was determined based on the 2 Ϫ ⌬ ⌬ CT method with normalization of the raw data to either 36b4 or Gapdh (see primer sequences in supplementary Table 1).…”

BMP7 Drives Human Adipogenic Stem Cells into Metabolically Active Beige Adipocytes

“…Adipose-derived stem cells ( h ASC) were isolated and cultured as we described previously [26]. h ASC from 4–5 different human subjects were pooled to reduce the individual variation.…”