| Tocotrienols (T3s) are unsaturated forms of vitamin E that have potent anti-inflammatory and anti-cancer properties. However, little is known of the T3s effects on obesity. Herein, 1) human adipose stem cells ( hASCs) were used to investigate the anti-adipogenic effects of T3s and underlying mechanism; 2) young C57BL/6J mice were used to study T3s effects on early onset obesity and insulin resistance; 3) the potential application of muscadine grape seed oils (MGSOs) to attenuate obesity and inflammation was investigated.;In hASCs, I found that gammaT3 exhibited the strongest effect among T3 isomers on inhibiting early-stage differentiation of adipocyte evidenced by marked decreases in adipogenic gene and protein expression and 90% triglyceride (TG) accumulation. Furthermore, gammaT3 treatment was found to inhibit anabolic signaling of Akt /mTOR, but activated the catabolic signaling of AMPK. Additionally, gammaT3 promoted autophagic process, which was not related to the AMPK activation. Continuous exposure to gammaT3 led to apoptotic cell death by increased PARP cleavage and caspase-3 activation. In mice, I found that gammaT3 was accumulated in adipose tissue and reduced weight gain in epididymal fat, mesenteric fat, and liver. Compared to high fat (HF) diet-fed mice, HF+gammaT3-fed mice had 1) decreased plasma levels of fasting glucose, insulin, and pro-inflammatory cytokines, 2) improved glucose tolerance, and 3) enhanced insulin signaling in adipose tissue. Additionally, gammaT3 treatment in adipocytes resulted in 1) suppression of MAP kinase and NFkappaB activation, and 2) restoration of insulin-stimulated glucose uptake. Furthermore, gammaT3 was discovered to reduce LPS-mediated M1 macrophage polarization in bone marrow stem cells. Finally, MGSOs were identified as a novel source of T3s with abundant alpha- and gamma-T3. MGSOs-treated hASCs had lower TG accumulation than that of cells treated with other edible oils. MGSOs-derived tocotrienol rich fraction (TRF) treatment significantly reduced mRNA and protein expression of crucial adipogenic genes (e.g., PPARgamma and aP2) in hASCs. Furthermore, TRF from MGSO markedly reduced LPS-induced pro-inflammatory gene (IL-6 and IL-8) expression in human adipocytes and cytokine secretion. Overall, these data suggest that gammaT3 is a potent agent to attenuate obesity and MGSOs may be used as a novel source to delivery its effects. |
