Differential modulation of biomarkers of metabolic syndrome in C57BL/6J mice by isomers of tocopherol
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Metabolic Syndrome (MetS) is increasingly becoming prevalent in industrialized countries and obesity and insulin resistance are principal risk factors. Antioxidant activities of tocopherols are well documented. However, it has become evident they exhibit other biologic activities. We investigated the effects of alpha (α) and gamma (γ) tocopherol on biomarkers of high-fat induced adiposity and insulin resistance in C57BL/6J mice and the mechanisms of action. In a preliminary study we reported that C57BL/6J mice could serve as excellent models of diet-induced obesity, MetS and its hepatic manifestation-non alcoholic steatohepatitis (NASH). Forty C57BL/6J mice, divided into control and high-fat groups, were fed low-fat diet and high-fat diets, ad libitum respectively for 20 weeks. At the end of 20 weeks, mice on high-fat diet developed hyperglycemia, hyperinsulinemia, hypoadiponectinemia along with elevated tumor necrosis factor (TNF-α), resistin, and free fatty acid levels that characterize MetS in humans. In this study, C57BL/6J mice (n=75) were divided into 5 groups and placed on five different dietary regimens as follows. Groups 1 and 5 (controls): low-fat (LF) and high-fat (HF) diets for 25 weeks, respectively; groups 2-4: HF diet for 15 weeks followed by 12 weeks on HF supplemented with αT, γT, αT + γT, respectively. Animals were sacrificed at the end of 27 weeks. α-T and αT + γT significantly reduced weight gain and improved insulin sensitivity indices. Protein expressions of adipocyte peroxisome proliferator activated receptor (PPAR-γ) and PPAR α were significantly higher in α-T and αT + γT groups (but not γT alone) than HF controls. This was associated with up regulation of expression of transport proteins and enzymes modulated by PPARs in these groups including adipocyte fatty acid binding protein 4 (FABP4), carnitine palmitoyl transferase (CPTIB, CPTII), β-oxidation enzymes including acetyl CoA Synthase-1 (ACSSI-1), acetyl CoA oxidase-1 (ACOX1), enoyl dehydrogenase-1 (EH-1), and medium chain acyl dehydrogenase (MCAD), and uncoupling protein (UCP-2). No significant differences were observed in expression of enzymes critical for lipogenesis including acetyl CoA carboxylase (ACC) and fatty acid synthase (FAS). Similar trend was observed in expression of hepatic FABP1, CPTIA, CPTII, ACSS-1, ACOX-1, EH-1, MCAD, and UCP-2 with no differences in expression of lipogenic ACC and FAS enzymes. In addition, significant improvement in insulin sensitivity was observed by increase in adiponectin (Acrp30) and concomitant decrease in tumor necrosis (TNF-α) expressions in the −T and αT + γT groups (but not γT alone). The study for the first time demonstrates the ability of αT (alone and in combination with γT) to function as dual PPAR agonist in modulating biomarkers of MetS in vivo.