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

BACKGROUND AND OBJECTIVE: We have previously demonstrated that gamma tocotrienol (gamma T3) potently inhibits adipocyte hyperplasia in human adipose-derived stem cells (hASCs). In this study, our objective was to investigate the gamma T3 effects on earlyonset obesity, inflammation and insulin resistance in vivo. METHODS: Young C57BL/6J mice were fed a high-fat (HF) diet supplemented with 0.05%.T3 for 4 weeks. The concentrations of gamma T3 in plasma and adipose tissue were measured using high-performance liquid chromatography. Effects of gamma T3 on body weight gain, adipose volume, plasma levels of fasting glucose, insulin (enzyme-linked immunosorbent assay (ELISA)), proinflammatory cytokines (mouse cytokine array), insulin signaling (western blotting) and gene expression (quantitative real-time PCR, qPCR) in the liver and adipose tissue were examined. Influences of gamma T3 on [H-3]-2-deoxyglucose uptake and lipopolysaccharide (LPS)-mediated NF kappa B signaling (western blotting) were assessed in hASCs. Effects of gamma T3 on macrophage M1/M2 activation were investigated using qPCR in mouse bone marrow-derived macrophages. RESULTS: After a 4-week treatment, gamma T3 accumulated in adipose tissue and reduced HF diet-induced weight gain in epididymal fat, mesenteric fat and the liver. Compared with HF diet-fed mice, HF+gamma T3-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 monocyte chemoattractant protein-1, indicating that gamma T3 reduced the recruitment of adipose tissue macrophages (ATMs). In addition, gamma T3 treatment in human adipocytes resulted in (1) activation of insulin-stimulated glucose uptake and (2) a significant suppression of MAP kinase and NF kappa B activation. In parallel, gamma T3 treatment led to a reduction of LPS-mediated M1 macrophage polarization. CONCLUSION: Our results demonstrated that gamma T3 ameliorates HF diet-mediated obesity and insulin resistance by inhibiting systemic and adipose inflammation, as well as ATM recruitment.