Gamma-tocotrienol attenuates high fat diet-induced obesity and insulin resistance by inhibiting adipose inflammation and M1 macrophage recruitment.

Zhao L, Kang I, Fang X, Wang W, Lee MA, Hollins RR, Marshall MR, Chung S.

Background and Objective:We have previously demonstrated that gamma tocotrienol (γT3) potently inhibits adipocyte hyperplasia in human adipose-derived stem cells (hASCs). In this study, our objective was to investigate the γT3 effects on early onset obesity, inflammation, and insulin resistance in vivo.Methods:Young C57BL/6 J mice were fed a high fat (HF) diet supplemented with 0.05% γT3 for 4 weeks. The concentrations of γT3 in plasma and adipose tissue were measured by HPLC. Effects of γT3 on body weight gain, adipose volume, plasma levels of fasting glucose, insulin (ELISA), pro-inflammatory cytokines (mouse cytokine array), insulin signaling (western blotting), and gene expression (quantitative real-time PCR, qPCR) in liver and adipose tissue were examined. Influences of γT3 on [3H]-2-deoxyglucose uptake and LPS-mediated NFκB signaling (western blotting) were assessed in hASCs. Effects of γT3 on macrophage M1/M2 activation were investigated by qPCR in mouse bone marrow-derived macrophages.Results:After a 4 week treatment, γT3 accumulated in adipose tissue and reduced HF diet-induced weight gain in epididymal fat, mesenteric fat, and liver. Compared to HF diet-fed mice, HF+γT3-fed mice were associated with 1) decreased plasma levels of fasting glucose, insulin, and proinflammatory cytokines, 2) improved glucose tolerance, and 3) enhanced insulin signaling in adipose tissue. There were substantial decreases in macrophage specific markers, and MCP1 indicating that γT3 reduced recruitment of adipose tissue macrophages (ATMs). Additionally, γT3 treatment in human adipocytes resulted in 1) activation of insulin-stimulated glucose uptake and 2) a significant suppression of MAP kinase and NFκB activation. In parallel, γT3 treatment led to a reduction of LPS-mediated M1 macrophage polarization.Conclusion:Our results demonstrated that γT3 ameliorates HF diet-mediated obesity and insulin resistance by inhibiting systemic and adipose inflammation, as well as ATM recruitment.

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Tocotrienol modulates crucial lipid metabolism-related genes in differentiated 3T3-L1 preadipocytes.

Burdeos GC, Nakagawa K, Abe T, Kimura F, Miyazawa T.

Obesity and other lipid metabolism-related diseases have become more prevalent in recent years due to drastic lifestyle changes and dietary patterns. Unsaturated vitamin E, tocotrienol (T3), represents one of the most fascinating naturally occurring compounds that has the potential to influence a broad range of mechanisms underlying abnormal lipid metabolism processes. However, its efficacy and mechanism have been uncertain due to scarcity of data concerning the effect of T3 on lipid metabolism. In this study, we report a series of fascinating experimental findings on how T3 affects lipid metabolism in differentiated 3T3-L1 preadipocytes. Treatment with T3 (25 μM), especially δ and γ isomers, inhibited the accumulation of triglyceride and lipid droplets in differentiated 3T3-L1 cells. This manifestation was supported by mRNA and protein expression of crucial lipid metabolism-related genes. The present study provides a novel set of data pertaining to the possibility of T3 as an anti-metabolic disorder agent.

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Tocotrienol Rich Fraction Reverses Age-Related Deficits in Spatial Learning and Memory in Aged Rats.

Taridi NM, Abd Rani N, Abd Latiff A, Wan Ngah WZ, Mazlan M.

Little is known about the effect of vitamin E on brain function. Therefore, in this study we evaluated the effect of tocotrienol rich fraction (TRF) on behavioral impairment and oxidative stress in aged rats. Thirty-six male Wistar rats (young: 3-months-old; aged: 21-months-old) were treated with either the control (olive oil) or TRF (200 mg/kg) for 3 months. Behavioral studies were performed using the open field test and Morris water maze (MWM) task. Blood was taken for assessment of DNA damage, plasma malondialdehyde (MDA) and vitamin E, and erythrocyte antioxidant enzyme activity. Brains were also collected to measure vitamin E levels. Results showed that aged rats exhibited reduced exploratory activity, enhanced anxiety and decreased spatial learning and memory compared with young rats. DNA damage and plasma MDA were increased, and vitamin E levels in plasma and brain were reduced in aged rats. Aged rats supplemented with TRF showed a markedly reduced level of anxiety, improved spatial learning and memory, reduced amount and severity of DNA damage, a reduced level of MDA, and increased levels of antioxidant enzyme activity and plasma/brain vitamin E compared with age-matched controls. In conclusion, TRF supplementation reverses spatial learning and memory decline and decreases oxidative stress in aged rats.

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Gamma-tocotrienol and hydroxy-chavicol synergistically inhibits growth and induces apoptosis of human glioma cells.

Abdul Rahman A, A Jamal AR, Harun R, Mohd Mokhtar N, Wan Ngah WZ.

Gamma-tocotrienol (GTT), an isomer of vitamin E and hydroxy-chavicol (HC), a major bioactive compound in Piper betle, has been reported to possess anti-carcinogenic properties by modulating different cellular signaling events. One possible strategy to overcome multi-drug resistance and high toxic doses of treatment is by applying combinational therapy especially using natural bioactives in cancer treatment.

METHODS:

In this study, we investigated the interaction of GTT and HC and its mode of cell death on glioma cell lines. GTT or HC alone and in combination were tested for cytotoxicity on glioma cell lines 1321N1 (Grade II), SW1783 (Grade III) and LN18 (Grade IV) by [3-(4,5-dimethylthiazol-2- yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfophenyl)- 2H- tetrazolium, inner salt] MTS assay. The interactions of each combination were evaluated by using the combination index (CI) obtained from an isobologram.

RESULTS:

Individually, GTT or HC displayed mild growth inhibitory effects against glioma cancer cell lines at concentration values ranging from 42-100 mug/ml and 75-119 mug/ml respectively. However, the combination of sub-lethal doses of GTT + HC dramatically enhanced the inhibition of glioma cancer cell proliferation and exhibited a strong synergistic effect on 1321N1 with CI of 0.55, and CI = 0.54 for SW1783. While in LN18 cells, moderate synergistic interaction of GTT + HC was observed with CI value of 0.73. Exposure of grade II, III and IV cells to combined treatments for 24 hours led to increased apoptosis as determined by annexin-V FITC/PI staining and caspase-3 apoptosis assay, showing caspase-3 activation of 27%, 7.1% and 79% respectively.

CONCLUSION:

In conclusion, combined treatments with sub-effective doses of GTT and HC resulted in synergistic inhibition of cell proliferation through the induction of apoptosis of human glioma cells in vitro.

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