开题报告内容：（包括拟研究或解决的问题、采用的研究手段及文献综述，不少于2000字）
Obesity has become one of the most prevalent health problems in the world today and the number of obese people is still growing rapidly. The largest increase has been in people with extreme obesity, those with BMI gt; 40, 45, and 50. Almost 6% of US adults have BMI gt; 40, and over 14% African American. With the increasing proportion of obese population, risks of type2 diabetes, fatty liver and other metabolic abnormality increase significantly as well. Obesity associated inflammation in adipose tissue triggers other related metabolic syndromes. Inflammation increases the secretion of proinflammation cytokines such as interleukin-6(IL-6) and tumor necrosis factor alpha(TNF-a) and decreases the secretion of anti-inflammation cytokines such as interleukin-10(IL-10), which in turn results in chronic low-grade inflammation. Macrophage infiltration and larger fat cells can be observed in inflamed adipose tissues.
Treatments of obesity include calorie-restriction, exercise and surgeries. Dietary interventions include the application of bioactive food compounds such as catechins and Vitamin E. Vitamin E consists of two classes of biologically active substances. All compounds in Vitamin E family have the common structural features with a chromanol head ring and a long hydrophobic side chain of 16 carbons. Tocophenols(T) are the major form of Vitamin E, with a saturated phytyl side chain, while tocotrienols(T3), the minor form of Vitamin E, possess an unsaturated isoprenoid side chain. According to there different structure patterns on the chromanol ring, both two groups can be further categorized as a,b,g and d. These two groups of biologically active substances have received a great deal of attention because of their potential health benefits.
Previous studies have shown that d-T3 and d-T potently prevent inflammation, obesity and carcinogenesis. d-T is methylated at the 8-position of the chromanol ring. Dietary sources like certain oils and nuts are rich in d-T. It has been demonstrated that d-T is more effective in inhibiting prostate cancer and cell proliferation than g- and a-T. Although it can protect cells from reactive oxygen species effectively, its effect on prostate cancer prevention is more due to specific inhibition of the receptor tyrosine kinase-induced activation of AKT, which reduces the pAKT levels. Compared with Ts, T3s are found distributed at higher rates in the lipid layer of cell membrane and diffuse more easily, which indicates that T3s can work better than Ts in inflammation and other metabolism syndromes like poor glucose tolerance, nonalcoholic fatty liver disease(NFLD) and abnormal serum cholesterol levels. Results from previous studies demonstrated that, d-T3 can improve the glucose tolerance in mice fed HF diet by alleviating the inflammation in adipose tissue and lowering the adiposity, but it did not change the body weight significantly. Additionally, d-T3 reduced the macrophage infiltration, which is responsible for the proinflammatory cytokine production in adipose tissue. Measured at the mRNA level, the d-T3 groups had a lower inflammatory cytokine level, as well as a higher anti-inflammatory cytokine level. After analysis of genes regulating lipid metabolism in adipose tissue and liver, d-T3s are found reduce fatty acid synthesis and increase fatty acid oxidation. In one study including high and low d-T3 doses, the high dose was more effective in lowering hepatic lipid synthesis, while the low dose enhanced the expression of genes associated with fatty acid oxidation. Besides, d-T3 can help prevent triglyceride accumulation and inflammation in liver, thereby improving hepatic function. However, more studies are required to dissect the differential effects of d-T3 in liver and different adipose cell types, and its effect on alteration of energy expenditure.
Green tea, a popular traditional beverage worldwide, is derived from the plant Camellia sinensis. The polyphenols in green tea are known as catechins, which includes the most abundant (-)-epigallocatechin-3-gallate (EGCG). EGCG serves as an antioxidant that can inhibit oxidation reaction in vivo and can help reduce the body weight gain, fasting blood glucose and insulin resistance. In addition, biological activities of lowering the lipids absorption, inhibiting lipid biosynthesis and promoting lipids catabolism have been demonstrated as well. EGCG alleviates the fatty liver significantly by inhibiting the absorption and activity of bile acid or affecting the microbes in the gastrointestinal tract. Expression of genes related to hepatic bile acid metabolism was obviously elevated by EGCG. However, studies also showed time-dependent changes in these effects.
Most previous studies have demonstrated the health benefits of tocotrienols with all isoforms, and the physiological function of EGCG and tocophenols have been fully investigated. To figure out the anti-inflammation effects of d-T3 and its behind mechanism, our study focuses specifically on the d-T3, d-T and EGCG are also used in different treatment groups for comparison. Hence, we use 0.05%d-T3, 0.05%d-T and 0.1%EGCG in three groups to determine if d-T3 can help better reduce high-fat induced obesity, insulin resistance, inflammation and cholesterol level in serum and liver than d-T, and the difference of its mechanism when compared with EGCG.
Male C57BL/6J mice at six weeks of age were purchased from Jackson Laboratory(Bar Harbor, ME, USA). All animal experiment procedures are performed in animal facilities of Department of Chemical Biology in accordance with the protocol 02-027 approved by the Institutional Animal Care and Use Committee of Rutgers, the State University of New Jersey. After one week of acclimation on AIN93M diet, the mice are randomly arranged into five diet treatment groups(10 mice per group): Group 1, normal low-fat(LF) diet, Group 2, high-fat(HF) diet with 60% calories from fat, Group 3, HF diet mixed with 0.05% d-T3(HF d-T3), Group 4, HF diet mixed with 0.05% d-T(HF d-T), Group 5, HF diet mixed with 0.1% EGCG(HFE). Mice were housed in 10 plastic cages, five mice per cage, with corncob bedding and were fed the respective diet for 16 weeks in a controlled room (temperature 24 to 25 ℃, humidity 70-75%, and lighting regimen of 12-h light-dark cycles). Body weight, water consumption and diet consumption were measured weekly, and cages were changed at the same time. Fasting blood glucose were tested at week 2,4,5,7,12 and 16. We collected the blood at week 8 and 12, and fresh fecal samples were collected weekly in the first 6 weeks. After 16 weeks, all the mice will be euthanized. Blood will be collected and then centrifuged for serum separation; adipose and liver tissue, intestine, colon and ileum will be dissected as well.
The experiment will end in the middle of May. After that, I will finish my thesis about this project and other related work.
References:
[1]Allen, L., et al. (2017). 'Effects of delta-tocotrienol on obesity-related adipocyte hypertrophy, inflammation and hepatic steatosis in high-fat-fed mice.' J Nutr Biochem 48: 128-137.
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