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www.mnf-journal.com Page 1 Molecular Nutrition & Food Research Received: 12 26, 2016; Revised: 05 25, 2017; Accepted: 05 26, 2017 This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1002/mnfr.201601122 . This article is protected by copyright. All rights reserved. Effects of green tea on lipid metabolism in overweight or obese people: A meta-analysis of randomized controlled trials Yuan Fen1, Dong Hui2, Fang Ke3, Gong Jing4, Lu fuer5 Institute of Integrated Traditional Chinese and Wertern Medicine, Tongji Hospital, Tongji Medical College,HuaZhong University of Science and Technology, Wuhan, Hubei430030, China Correspondence: Lu fuer (felu@tjh.tjmu.edu.cn ) Keywords: green tea/ lipid metabolism/ meta-analysis/ overweight/ obese Abbreviations: TG, triglyceride; TC, total cholesterol; EGCG, epigallocatechin gallate Scope: The effects of green tea on lipid metabolism were inconsistent. The objective of this meta-analysis was to evaluate the effects of green tea on lipid metabolism in overweight or obese people. Methods and results: We searched randomized controlled trials(RCTs) comparing green tea with a control on lipid metabolism on PUBMED and WEB OF SCIENCE (January 1990 to September 2016), COCHRANE and EMBASE (updated to https://doi.org/10.1002/mnfr.201601122 https://doi.org/10.1002/mnfr.201601122 https://doi.org/10.1002/mnfr.201601122 mailto:felu@tjh.tjmu.edu.cn%20(F www.mnf-journal.com Page 2 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 2 October 2016), and the Chinese databases CNKI, WanFang and CBMD. Twenty- one articles studying 1704 overweight or obese subjects were selected for this meta-analysis. The pooled results demonstrated that green tea significantly decreased plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDL) levels in overweight or obese people. The weighted mean difference was - 3.38mg/dl for TC (95% CI: -6.42, -0.33mg/dl) and -5.29mg/dl for LDL (95% CI: - 7.92, -2.66mg/dl), respectively. Green tea intake, however, showed no effect on plasma triglyceride (TG) and high-density lipoprotein cholesterol(HDL) levels in overweight or obese people with a relatively high heterogeneity. Conclusions: The meta-analysis shows that drinking green tea can lower plasma TC and LDL levels significantly. Nevertheless, green tea’s effect on plasma TG and HDL must be further evaluated by additional high-quality and large-scale RCTs. www.mnf-journal.com Page 3 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 3 GA-TEXT The flowchart shows the results of serching on the databses and the conclusions of this meta-analysis. 1 Introduction Obesity or overweight is a global health problem that results from the interaction of eating habits with genetic and environmental factors that lead to energy imbalance[1]. Based on WHO statistics, the prevalence of overweight or obesity has increased twofold since 1980 and 52% of people aged 18 years and over were either overweight or obese in 2014[2]. In the USA, beyond two-thirds (68.8%) adults are diagnosed as either overweight (33.1%) or obese (35.7%)[3]. Spending on obesity is enormous in America and has become a large financial burden for society[4]. In www.mnf-journal.com Page 4 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 4 Europe, over 50% of the population is overweight or obese. The situation is exacerbated by the fact that the incidence of overweight or obesity in children and adolescents is surging[5]. Moreover, many countries consider obesity to be a disease and take action on treatment rather than prevention[6]. In America and Europe, overweight and obesity are defined as BMI >25 kg/m 2 or 30 kg/m2. In Asia, those whose BMIs are over 23kg/m2 or 25kg/m2 will be diagnosed as overweight or obese[7]. A series of studies about the relationship between obesity or overweight and dyslipidemia have been performed. Based on recent reports, obesity is harmful to lipid metabolism and causes dyslipidemia[8-11]. Dyslipidemia, which is the primary risk for cardiovascular diseases, is defined as an increase of plasma triglyceride (TG) or low-density lipoprotein cholesterol (LDL) or a decrease of plasma high- density lipoprotein cholesterol (HDL)[12]. Increasing plasma LDL levels in the blood contribute to the development of atherosclerosis[13], and plasma HDL, which has a positive effect on myocardial infarction, is clearly reduced in dyslipidemia and loses its protective function against vascular disease[14]. Additionally, the increasing ratio of total cholesterol to HDL is the optimal marker of cardiovascular disease[15]. To decrease the risk of cardiovascular disease, medications including niacin and omega-3 fatty acid and statins are frequently used to alleviate dyslipidemia; however, their adverse effects, which include headaches, flushing, liver injury and abnormally high LDL, attract negative public attention[16-19]. A more effective and safe substance should be studied and applied to prevent and treat dyslipidemia. Tea, from Camellia Sinenis, is a popular beverage around the world, especially in www.mnf-journal.com Page 5 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 5 Asia, North Africa, the USA and Europe [20]. Tea can be classified as green tea, oolong tea or black tea depending on the manufacturing process. As a consequence, the ingredients across these types differ. Specifically, green tea is abundant with kaempferol glycosides, while oolong tea contains more quercetin and myricetin glycosides and black tea is rich in quercetin glycosides[21]. The benefical effects of tea on human health and fitness, however, is attributed to green tea, specifically its main component, catechin[22]. Catechin is a vital compound that contains epigallocatechin gallate (EGCG), epicatechin gallate (ECG), epigallocatechin (EGC), and epicatechin (EC)[23]. Of these, EGCG is the major and functional component[24]. Generally, the proportion of catechin is 30–42% of the dry green tea leaves (e.g., 2.5 g of tea leaves in 250 mL hot water holds 240–320 mg of catechin), and 60–65% of catechin is EGCG[25]. According to recent studies, green tea could function to mitigate inflammation, hypertension and some cancers[26-28]. Moreover, many studies have shown that green tea has a positive effect on the metabolism of lipid by different mechanisms. Huang proved that green tea could reduce food intake and lipid absorption[29]. Wang and Sae-tan concluded that green tea catechins restrained the proliferation of adipocytes and the accumulation of TG[30, 31]. Suzuki-Sugihara demonstrated that green tea catechins could decrease LDL oxidation to reduce cardiovascular risk[32]. Controversies remain, however, regarding the effects of green tea on plasma lipid metabolism as demonstrated in clinical trials, especially for overweight or obesity. Some clinical experiments show that green tea consumption has no effect on any lipid profiles[33-41], while other clinical studies show that its effects on lipid www.mnf-journal.com Page 6 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 6 metabolism are significant[42-52]. Moreover, there has been no meta-analysis of the effect of green tea on lipid metabolism in the overweight or obese. Thus, we perform this meta-analysis to evaluate the effects of greentea on lipid metabolism in people with overweight or obesity based on published randomized controlled trials that only recruited subjects who are overweight or obesity. This analysis may help us to find an effective alternative to regulate the lipid metabolism. 2 Subjects and methods 2.1 Search and selection PUBMED and WEB OF SCIENCE (January 1990 to September 2016), in addition to COCHRANE, EMBASE, the Chinese databases CNKI and WanFang and CBMD (updated to October 2016) were utilized to search randomized controlled trials (RCTs) on the effects of green tea on lipid metabolism. The key words consisted of green tea, Camellia Sinensis, green tea extract, tea polyphenol*, catechin, epigallocatechin gallate, EGCG, epicatechin gallate, ECG, epigallocatechin, EGC, epicatechin, EC, lipid*, triglyceride, TG, total cholesterol, TC, low density lipoprotein cholesterol, LDL-C, high density lipoprotein cholesterol, HDL-C, lipid metabolism, glucose, diabetes mellitus, insulin, glycemic, metabolic syndrome, MS, glycaemic, and non insulin dependent diabetes mellitus. The search was limited to clinical trials with human subjects. Studies were selected for this meta-analysis if they met the following criteria: (i) The duration of intervention was over 2 weeks; (ii) Green tea or green tea exact was the only supplement used, rather than mixing green tea with other subjects such as oolong tea, black tea or grape seeds; (iii) The participants were overweight www.mnf-journal.com Page 7 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 7 (BMI>25kg/m2 in America and Europe or 23kg/m2 in Asia) or obese (BMI >30kg/m2 in America and Europe or 25kg/m2 in Asia); (iv) Parallel or crossover RCTs in human beings were conducted; (v) All data were available including the baseline and endpoint values or net changes between them with mean, standard deviation, and number of participants available, or 95% confidence intervals for the experimental and control groups; (vi) All studies had to contain at least one of following statistics: plasma TG, TC, LDL or HDL levels; and (vii) The trials had to show the comparison between the treatment and control groups. 2.2 Quality assessment The Jadad scale was used to assess the quality of selected studies[53]. The items were shown as follows: (1) process of randomness (0-2 points); (2) double-blinding (0-2 points); (3) concealment of allocation (0-2 points); and (4) reporting dropouts and withdrawals (0-1 points). The score of the high-quality study was four or more. 2.3 Data collection The following data were collected from the studies (see Table 1 and Supporting Information Table 1): 1) Study characteristics, including authors, publication year, study design, dose, and periods of intervention, formulation of green tea, Jadad score, decaffeination of green tea, percentage of caffeine and EGCG dose; 2) Participants’ information including countries of origin, average ages, BMI, physical condition, and type of lifestyle; 3) Study outcomes, including plasma TG, TC, LDL, and HDL. All lipid values were transferred into mg/dl, and the index of the conversion formula was as follows: 1) 1mmol/l TG=88.6mg/dl TG; 2) 1mmol/l TC or LDL or HDL =38.7mg/dl TC or LDL or HDL. If trial included different doses of green tea treatment www.mnf-journal.com Page 8 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 8 groups, we divided them into two trials with the same control group[53]. If trial contained several different treatment groups that were compared with a control group, we only extracted the information on the green tea or green tea extract and control groups. If trial was designed with crossovers, we only extracted the first stage data before the subjects were told to exchange interventions[54]. For inaccurate data, we contacted study authors via emails to request their original data. We excluded those studies whose authors refused to provide original data. 2.4 Statistics and analysis STATA software (version 14; StataCorp) was applied for our meta-analysis. The outcomes of net change between the treatment groups and control groups were shown with weighted mean differences (WMD) and 95% CI for TG, TC, LDL, and HDL. The heterogeneity between studies was assessed using Cochrane’s test (p<0.1). The I2 was checked; we considered I2>50% to indicate high heterogeneity between studies and the corresponding p-value >0.1 was considered low heterogeneity[55]. The outcomes were generated from a fixed-effects model if the I2<50%, otherwise, a random-effects model was used to analyse data. Z-scores were used to evaluate overall effects. The overall effect was reckoned with statistic meaning when the linked p value was less than 0.05. Publication bias and sensitivity analysis were assessed using Egger’s regression test. 2.5 Subgroup analysis The purpose of subgroup analysis was to discover the source of heterogeneity. Thus, we conducted seven subgroups to analyse the heterogeneity, including the duration of intervention (≥12weeks or <12weeks); dose of EGCG (EGCG≥400 or www.mnf-journal.com Page 9 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 9 <400mg); continent (America, Europe or Asia); decaffeination of green tea or not; the Jadad score (≥4 or <4); subjects with or without a hypocaloric diet; and participants with or without complications. The exercise subgroup was not conducted because of small sample size of trials available for this meta-analysis. 3 Results A total of 1058 English articles and 394 Chinese articles were searched. Nine hundred and seventy-eight articles were excluded(272 duplicated articles; 20 no placebo articles; 81 cell; 109 other animals; 650 no relation; 47 green tea or green tea extract mixing with others; 66 only other tea; 129 reviews) after reading titles and abstracts. An initial, 78 articles were selected. After further sifting, 21 articles were selected to complete the meta-analysis: 15 articles including 18 trials for TG[33, 35, 37, 40-47, 50, 52, 56, 57] , 18 articles including 21 trials for TC[33-37, 39-47, 51, 52, 56, 57], 19 articles including 21 trials for LDL[33-37, 39-49, 51, 52, 57], and 20 articles including 22 trials for HDL[33-37, 39-52, 57]. The process is presented in Figure 1. 3.1 Study characteristics In total, 21 articles including 24 trials enrolling 1704 subjects were included, with 866 participants in the treatment group and 838 subjects in the control group. The study attributions are shown in Table 1. All of the subjects were overweight or obese. In details, trials tested following: six trials enrolled people with early metabolic syndrome, borderline metabolic syndrome or defined metabolic syndrome; three trials enrolled people with type 2 diabetes; two trials enrolled people with hypertension; and another thirteen trials enrolled people with only overweight or www.mnf-journal.com Page 10 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 10 obesity. Seven trials were conducted in Asia; eleven trials were performed in Europe, and the remainder occurred in America. The ages of participants varied from 6 to over 80 years. The periods of treatment ranged from six weeks to twenty-four weeks. The dosage of EGCG reported was from 39 mg to 856.8 mg per day, and six trials did not describe the specific dosage of EGCG. All of the trials were RCTs. Twenty-two were parallel trials, of which thirteen were double blind, five were single blind, and four were non-blind. Two were crossover trials, one of which was double- blind and the other was non-blind. One trial conducted by Maki[52] required people to exercise, and fourtrials restrained to energy intake[34, 35, 49, 51]. One trial asked participants to refrain from dieting but to exercise[50]. Other trials were keeping usual lifestyle but limited to ingest extra green tea, green tea supplements or catechin-rich food. Nine trials were of high quality (Jadad score ≥ 4)[33, 34, 36, 39, 42, 44, 46-48]. The percentage of caffeine, which was similar in most paired treatment and control groups, varied from 0 to 79.4% and 77.7% in treatment and control groups respectively. However, four trials did not reported the exact percentage of caffeine in both groups[37, 51, 56]. Publication bias was estimated by Egger’s test. Studies with p values over 0.05 were considered to exhibit low bias. The outcomes demonstrated that there were insignificant publication bias of TG, TC, LDL and HDL(TG Egger’s test: P=0.202; TC Egger’s test: P=0.617; LDL Egger’s test: P=0.812; HDL Egger’s test: P=0.647). (Supporting Information Figure 1). www.mnf-journal.com Page 11 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 11 3.2 Effect of green tea on plasma TG levels among people with overweight or obesity Eighteen trials with 584 subjects in the treatment group and 553 in control group reported baseline data and endpoint values regarding plasma TG levels. Under a fixed-effects model, the average change in TG values between the treatment and control groups was -7.02mg/dl (95% CI:-14.58, 0.54mg/dl). The heterogeneity I2 (variation in WMD attributable to heterogeneity) was 28.5% and the related p-value was 0.126. The Z score was 1.82 and the corresponding p-value was 0.069. This suggested green tea had no significant effect on plasma TG levels in people with overweight or obesity (Figure 2). 3.3 Effect of green tea on plasma TC levels among people with overweight or obesity Twenty-one trials analysed the effect of green tea on plasma TC levels. 744 overweight or obese people were in the experimental group and 710 participants were in the control group. Under a fixed-effects model, the net change between two groups was significant, as the data show: -3.38mg/dl (95% CI: -6.42, -0.33mg/dl) (Figure 3). The heterogeneity I2 (variation in WMD attributable to heterogeneity) was 0.0% and the related p-value was 0.549. The Z score was 2.17 and the corresponding p-value was 0.03. According to these results, green tea showed beneficial effects on decreasing plasma TC levels in people with overweight or obesity. www.mnf-journal.com Page 12 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 12 3.4 Effect of green tea on plasma LDL levels among people with overweight or obesity Twenty-one trials were selected to perform the analysis. There were 726 and 712 subjects in the intervention and control groups, respectively. We used a fixed-effects model to analyze the data. As a consequence, there was a remarkable decrease in plasma LDL levels. The difference between the two groups was -5.29mg/dl (95% CI: -7.92, -2.66mg/dl) (Figure 4). The heterogeneity I2 (variation in WMD attributable to heterogeneity) was 1% and the related p-value was 0.588. The Z score was 3.94 and the corresponding p-value was 0.000. 3.5 Effect of green tea on plasma HDL levels among people with overweight or obesity Twenty-two trials containing 1534 subjects (772 of them in the treatment group, the remainder in the control group) were used to analyse the effect of green tea on plasma HDL levels. With a random-effects model, the net change between the treatment and control groups was 1.13mg/dl (95% CI: -0.24, 2.51mg/dl) (Figure 5). The heterogeneity I2 (variation in WMD attributable to heterogeneity) was relatively high at 51.4%, and the related p-value was 0.002. The Z score was 1.62 and the corresponding p-value was 0.105. 3.6 Analysis of subgroup and sensitivity The outcomes of TG, TC, LDL, HDL are shown in the Supporting Information Tables 2, 3, 4 and 5, respectively. According to the attributions of participants, we conducted seven subgroups to analyse the source of heterogeneity, which included the dosage of EGCG, duration of intervention, continents, complications, diets, the www.mnf-journal.com Page 13 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 13 quality of study and decaffeination. In the dosage subgroup, there was no heterogeneity for all lipid values in the high subgroup (EGCG≥400mg/d). However, green tea only showed significant effects on plasma LDL levels in this subgroup. We also analysed the subgroup of the duration of each intervention. An obvious benefit occurred in the long-term subgroup (≥12weeks) for plasma TC, LDL and HDL levels, but not for plasma TG levels. In the complication subgroup, green tea showed powerful effects on plasma LDL level in subjects with or without complications. In addition, we found a benefit of green tea for TG with low heterogeneity in trials that enrolled subjects with other complications. Nevertheless, a large decrease in plasma TC levels was found in the subgroup of the subjects without complications. In the subgroup stratified by continents, green tea had significant benefits on TG in the Europe subgroup and on LDL in both the Asia and Europe subgroups. In the subgroup divided by decaffeination, green tea consumption showed an obvious benefit for plasma TG levels in the decaffeination subgroup; however, it had a powerful effect on plasma LDL levels not only in the decaffeinated subgroup but also in the undecaffeinated subgroup. In the subgroup of hypocaloric diet, the green tea supplement showed a lowering effect on plasma HDL levels. A powerful effect of green tea on plasma TC and LDL levels was also shown in isocaloric diet subgroup. In Jadad score subgroup, green tea was only good for lowering plasma TG levels in the high quality subgroup (Jadad score ≥4) and for plasma LDL levels in both high(Jadad score ≥4) and low (Jadad score <4)quality subgroups. The results of the sensitivity analysis of lipid parameters were detected with STATA software. The pooled effects of trials were analogous (Supporting www.mnf-journal.com Page 14 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 14 Information Figure 2). 4 Discussion This meta-analysis is the first to study the effects of green tea on lipid parameters in overweight or obese people. Although some meta-analysis have shown that green tea had significant effects on TC and LDL but no effect on TG and HDL[58-60], not all of them examine the effects of green tea on lipid metabolism in overweight or obese people. Whether green tea has a more profound influence on lipids metabolism in overweight or obese people is unclear. According to the outcomes, green tea could significantly decrease plasma TC and LDL levels, but, it is not good for TG and HDL. Those results may suggest that green tea carries no additional benefits for overweight or obese subjects. Although the results for plasma HDL showed a duration-dependent effect of green tea according to the analysis of the duration subgroup, the heterogeneity is significant (63%). Thus, the results did not demonstrate that long-term green tea intake could better modulate the lipid metabolism in overweight or obese people. Previous studies reported that EGCG was the major hypolipidemic component in green tea, and its mechanisms may be associated with decreasing the absorption of lipids and attenuating inflammation[61-63]. Therefore, we performed the subgroup analysis of the dosage of EGCG to detect whether green tea had more significant effects on levels of plasma lipids with a high dosage of EGCG. To our surprise, green tea only showeda benefit for decreasing the plasma LDL levels in both high(≥400mg/d) and low (<400mg/d) dosage of EGCG subgroups, but not for other lipid parameters(TG, TC, HDL) in the blood. Even, the high dose EGCG did not www.mnf-journal.com Page 15 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 15 significantly alleviate TC levels, which conflicted with the meta-analysis[64]. This may suggest that 400mg/d was not reasonable critical value to define a high or low subgroup for overweight or obese people. Moreover, several trials did not report the exact dose of EGCG. Therefore, the dose-different impact of EGCG must be studied further. There is a close relationship between diet and lipid metabolism; therefore, we conducted a subroup analysis of calories. Green tea consumption showed no benefit for plasma TG levels in the hypocaloric diet subgroup. This may conflict with the article that demonstrated dietary interventions had beneficial effects on plasma TG levels[65]. It could not be denied, however, that a hypocaloric diet was not good for blood lipid profiles because only two trials were included in hypoclaric subgroup. What was surprising was that the green tea showed significant effects on plasma TC and LDL levels in the isocaloric diet subgroup with no hetergeneity, rather than in the hypocaloric diet subgroup. Although the outcomes were inconsistent with the conclusion of Sonego, who demonstrated that a healthy diet was good for lipid metabolism[66], we could infer that the green tea definitely had good effects on plasma TC and LDL levels. The main reason that the green tea had no effects on plasma TC and LDL levels might be the small number of subjects included in the hypocaloric diet subgroup. Hence, more studies enrolling subjects with a hypocaloric diet are needed to research the relationship between diet and lipid metabolism. Caffeine, one of the bioactive components of green tea, has been demonstrated to reduce plasma cholesterol and TG levels[67]. Thereby, a subgroup stratified by decaffeination was performed to analyse whether green tea components of caffeine www.mnf-journal.com Page 16 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 16 and green tea catechins exerted synergistic effect on lipid metabolism in overweight or obese people. Surprisingly, green tea had a significant effect on plasma LDL levels in the both decaffeinated and undecaffeinated subgroups. In contrast with the undecaffeinated subgroup, however, green tea showed an obvious benefit to plasma TG levels in the decaffeinated subgroup. The result partly conflicted with the animal experiment performed by Zhao, which showed that the combination of caffeine and catechins improves the metabolism of lipids through activating the corresponding enzymatic bio-activities[68]. The reason for this outcome may be that most participants in the selected trials did not limit their intake of caffeine from other foods or beverages so that the effect of green tea on TG in the decaffeinated subgroup was reversed. In addition, the subjects we included varied from healthy overweight or obese individuals to unhealthy overweight or obese individuals experiencing complication from diabetes, metabolism syndrome or hypertension. We conducted a complications subgroup analysis to detect the heterogeneity. An interesting phenomenon was found in TG group. In the subgroup with complication, the green tea showed a statistically significant difference on TG but had no such effect in the subgroup without complications. This may suggest that the effect of green tea on TG is more pronounced in overweight or obese individuals who may be with higher plasma TG. There are several limitations in our meta-analysis. First, more than half of trials were low-quality (Jadad score <4). Therefore, it may cause false positive or false negative results in this subgroup because of subjectivity. For instance, although www.mnf-journal.com Page 17 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 17 green tea did not show good results for plasma TG levels overall, it had an obvious shrinking effect on plasma TG levels in the high quality subgroup. More high quality studies are necessary to analyse the effects of green tea on lipid metabolism in overweight or obese people. Second, the ages of subjects ranged from children to the elderly, and the green tea supplement offered to the subjects varied from pure EGCG to green tea without purity. Other components included in green tea also have a positive effect on lipid parameters[69]. All of these factors may contribute to the heterogeneity. Third, some studies did not report the exact dosage of EGCG that might cause the paradoxical effect in the dosage subgroup analysis. Additionally, some articles were excluded for the unavailable data[70, 71], and the search was limited to the English and Chinese databases that may confound the outcomes. Finally, although the adverse affairs of green tea had been reported in some trials [33, 34, 44, 46], most of the subjects in the trials would heal without treatment in the first week of intervention, and few people stopped participating for this reason. This finding demonstrated that the safety of green tea was great even for long-term or heavy dosage. In conclusion, our meta-analysis suggested that green tea was good for decreasing plasma TC and LDL levels in overweight or obese people, especially for long-term consumption. The effects of green tea on decreasing plasma TG and increasing HDL levels were not supported, however, although green tea showed a positive effect on them in some subgroups. More high-quality and long-term trials are needed for further characterisation of the effects of green tea on serum lipids in overweight or obese people. www.mnf-journal.com Page 18 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 18 Y.F designed the study and wrote this article; F.K. an G.J searched reference and extracted data; D.H. and L.F gave pertinent advices and careful revision. This article is supported by the National Natural Science Foundation of China (No. 81473637, 81373871, 81673928). There is no conflict of interests among the authors. www.mnf-journal.com Page 19 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 19 5 References [1] Cheng, T. O., Obesity crisis comprised of danger and opportunity. J. Am. Diet. Assoc. 2004, 104, 1546. [2] Kang, Y. J., Wang, H. W., Cheon, S. Y., Lee, H. J., et al., Associations of Obesity and Dyslipidemia with Intake of Sodium, Fat, and Sugar among Koreans: a Qualitative Systematic Review. Clin. Nutr. Res. 2016, 5, 290-304. [3] Flegal, K. M., Carroll, M. D., Kit, B. K., Ogden, C. L., Prevalence of Obesity and Trends in the Distribution of Body Mass Index Among US Adults, 1999-2010. 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Sci. 2006, 51, 298-303. [70] Eichenberger, P., Mettler, S., Arnold, M., Colombani, P. C., No effects of three- week consumption of a green tea extract on time trial performance in endurance- trained men. Int. J. Vitam. Nutr. Res. 2010, 80, 54-64. [71] Chan, C. C., Koo, M. W., Ng, E. H., Tang, O. S., et al., Effects of Chinese green tea on weight, and hormonal and biochemical profiles in obese patients with polycystic ovary syndrome--a randomized placebo-controlled trial. J. Soc. Gynecol. Investig. 2006, 13, 63-68. www.mnf-journal.com Page 28 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 28 Table 1 The characteristics of studies and participants included in this meta- analysis. Study Country Study design Hsu et al.(2011) China RP; DB Nagao et al.(2007) Japan RP; BD Chen et al.(2016) China RP; DB Matsuyama et al.(2008) Japan RP; DB Mielgo-Ayuso et al. (2014) Spain RP; DB Diepvens et al.(2006) Netherlands RP; DB Hsu et al.(2008) China RP; DB Stendell-Hollis et al.(2010) USA RP; DB Bogdanski et al.(2012) Poland RP; DB Suliburska et al.(2012) Poland RP; DB Brown et al. (2009) UK RP; DB Senger et al.(2012) Brazil RP Mousavi et al.(2013)a Germany RP Mousavi et al.(2013)b Germany RP Brown et al.(2011) UK RC; DB Pierro et al.(2009) Italy RC Belcaro et al.(2013) Italy RP; SB Basu et al.(2011)a USA RP; SB Basu et al.(2011)b USA RP; SB Sanchez et al.(2005)a USA RP; SB Sanchez et al.(2005)b USA RP; SB Maki et al.(2009) USA RP; DB Tsai et al.(2009) China RP Tsuchida et al.(2002) Japan RD; DB www.mnf-journal.com Page 29 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 29 Table 1 continued Number of subjects (treatment/control) Age of participants(year) ,mean±SD,(treatment/co ntrol) BMI(treatment/control) kg/m2 35/33 50.5 ±9.2/52.2±9.1 30.3±4.3/29.2±3.6 123/117 41.7 ± 9.9 26.9±1.9/26.7±2.1 39/38 44.1±10.9/44.9±11.9 31.0±3.8/30.0±3.5 19/19 6–16 27.2±3.67/27.4± 3.92 43/40 33.7±2.6 /34.3±3.0 30-40 23/23 41.7±8.6/41.6±10.0 27.7±1.8/27.7±1.8 41/37 43.0 ±11.1/43.9±12.631.2±3.5/30.5±4.6 23/16 56.6±8.1/57.8±8.5 31.0±4.3/28.7±3.8 28/28 49.2±8.8/51.5±7.4 32.5 ± 3.3/33.9 ± 2.3 23/23 48.56±8.81/52.26±7.71 32.07±2.41/33.45±2.65 46/42 52.15 ±6·43/50.57±6.48 31.21±2.80/30.96±2.45 24/21 ≥60 30.5±4.3/30.4±4.5 24/14 54.6±9.6/52.0±8.2 27.4±2.8/28.1±3.0 25/14 56.2±8.5/52.0±8.2 28.1±3.3/28.1±3.0 67/70 49.5±5.6/49.4±5.6 31.7±2.7/31.4±2.6 50/50 25-60 28-36 48/50 47.6 ±5.5/45.3±3.55 31.0±2.0/30.9±2.6 13/12 42.8±9.4/44.6±11.1 36.1±1.3 10/12 39.5±9.5/44.6±11.1 36.1±1.3 7/11 >21 38.6±1.5/37.4±2.8 5/11 >21 41.5±2.1/37.4±2.8 51/56 21-65 32.2±0.5/32.2±0.5 60/60 25-65 35-38 39/41 30-65 24-30 www.mnf-journal.com Page 30 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 30 Table 1 continued Dosage of EGCG(mg/d) Duration of intervention Green tea decaffeinated Percentage of caffeine (%)(treatment/control) 856.80 16 weeks yes None 103.00 12 weeks no 72.3/ 75.0 856.80 12 weeks yes None 102.50 24 weeks no 79.4/ 77.7 300.00 12 weeks yes None 595.80 87 days no 16.4/ 0 377.15 12 weeks no 0.69/ 0 128.80 6 months yes None 208.00 3 months yes None 208.00 3 months yes None 800.00 8 weeks yes None Unclear 60 days no Unreported Unclear 8 weeks no Unreported Unclear 8 weeks no Unreported 430.00 6 weeks yes None Unclear 90 days yes None Unclear 24 weeks yes None 440.00 8 weeks yes None 500.00 8 weeks yes None 400.00 8 weeks yes None 500.00 8 weeks yes None 214.00 12 weeks no 7.8/ 7.8 Unclear 12 weeks no Unreported 115.00 12 weeks no 24.4/ 23.9 www.mnf-journal.com Page 31 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 31 Table 1 continued Physical condition Jadad score Daily dosage of treatment/control Obesity with T2DM 7 1500mg decaf-GTE/ cellulose Visceral fat-type obese 3 9g GT/ control Central obesity 7 1500mg decaf-GTE/ cellulose Obese/near-obese 3 576 mg catechins/ 75mg catechins Pre-menopausal obese 7 300mg EGCG/ lactose. Overweight 3 1443.6mg GT/ placebo Obese 7 1200mgGTE/ placebo Overweight/obese 5 960ml decaf-GT/ placebo Obese with hypertensive 4 379mg GTE/ placebo Obese with hypertension 5 379mg GTE/ placebo Overweight/ obese male 5 800mg EGCG/ placebo Metabolic syndrome 3 3g GT/ placebo Overweight/ obese with T2DM 2 4cups GT/ control Overweight/ obese with T2DM 2 2cups GT/ control Overweight and obese 7 800mg decaf-catechins/ placebo Obese 1 300mg GTE/ placebo Borderline for MS 2 300mg GT catechin/ placebo Obese with MS 2 4cups GT/ water Obese with MS 2 2capsules GTE/ water MS 2 4cups GT Beverage/ water MS 2 2capsules GTE/ water Overweight and obese 2 625mg catechins /control beberage Obese 1 6g GT/ control Overweight or obese 2 588mg catechin/126mg catechin www.mnf-journal.com Page 32 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 32 Table 1 continued Formulation Lifestyle Capsure Usual lifestyle Beverage Usual lifestyle Capsure Usual lifestyle Beverage Usual lifestyle Capsule Hypocaloric diet Capsule Hypocaloric diet Capsule Usual lifestyle Beverage Usual lifestyle Capsule Usual lifestyle Capsule Usual lifestyle Capsule Usual lifestyle Beverage Usual lifestyle Beverage Usual lifestyle Beverage Usual lifestyle Capsule Usual lifestyle Tablet Hypocaloric diet Tablet Exercise and hypocaloric diet Beverage Usual lifestyle Capsule Usual lifestyle Beverage Usual lifestyle Capsule Usual lifestyle Beverage Exercise Powder Hypocaloric diet Beverage Usual lifestyle RP, random parrallel trial; RC, random crossover trail; DB, double-blinding; SB, single-blinding; GTE, green tea extract; decaf-GTE, decaffeinated green tea extract EGCG, epigallocatechin gallate; GT, green tea, decaf-GT, decaffeinated green tea ; decaf-catechins, decaffeinated catechins; T2DM, type 2 diabetes mellitus; MS, metabolic syndrome www.mnf-journal.com Page 33 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 33 Figure 1. Flowchart showing the process of selecting, including, and excluding articles by individuals for this meta-analysis. www.mnf-journal.com Page 34 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 34 Figure 2. Effect of green tea compared with control on plasma triglyceride levels. Weight was analysed with STATA software by using the number of participants, mean and SD in treatment and control groups. The diamond indicates the pooled effect, and the outcome was obtained from a fixed-effects model. WMD, weighted mean differences. www.mnf-journal.com Page 35 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 35 Figure 3. Effect of green tea compared with control on plasma total cholesterol levels. Weight was analysed with STATA software by using the number of participants, mean and SD in treatment and control groups. The diamond indicates the pooled effect, and the outcome was obtained from a fixed-effects model. WMD, weighted mean differences. www.mnf-journal.com Page 36 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 36 Figure 4. Effect of green tea compared with control on plasma low-density lipoprotein cholesterol levels. Weight was analysed with STATA software by using the number of participants, mean and SD in treatment and control groups. The diamond indicates the pooled effect, and the outcome was obtained from a fixed- effects model. WMD, weighted mean differences. www.mnf-journal.com Page 37 Molecular Nutrition & Food Research This article is protected by copyright. All rights reserved. 37 Figure 5. Effect of green tea compared with control on plasma high-density lipoprotein cholesterol levels. Weight was analysed with STATA software by using the number of participants, mean and SD in treatment and control groups. The diamond indicates the pooled effect, and the outcome was obtained from a random- effects model. WMD, weighted mean differences.