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.
