Metabolic syndrome (MetS) is a significant public health problem worldwide and approximately 34% of adults in the United States meet the criteria for metabolic syndrome according to the National Cholesterol Education Program’s Adult Treatment Panel III (guidelines . According to the American Association of Clinical Endocrinologists and the International Diabetes Federation metabolic syndrome is defined as a complex of symptoms that includes having elevated waist circumference (> 102 cm in men and > 88 cm in women) and two or more of the following factors: elevated serum of triglycerides, dysglycemia, elevated blood pressure, and reduced serum of high-density lipoprotein (HDL) associated cholesterol . Persons exhibiting MetS also commonly have obesity-related fatty liver disease (ORFLD) and ORFLD is now widely accepted as the hepatic component of the metabolic syndrome [3-5]. MetS greatly increases risk for chronic disease such as cardiovascular disease, cancer, and others.
Consumption of a high-fat diet is a strong risk factor for the development of obesity and metabolic syndrome. Epidemiological studies have shown that obesity is generally more prevalent in societies that consume a Western-style diet, which, in addition to being deficient in several nutrients, is also high in fat (30-40% of kcal in diet) [6-8]. Dietary, pharmacological, and surgical strategies have been developed in the last decade to prevent the metabolic effects of a high-fat diet. These methods control food intake, increase energy expenditure, promote fat oxidation in the body, or inhibit fat absorption into the body. Pharmacological treatment for the metabolic syndrome often consists of separate drugs targeted at the individual symptoms of the disease . Despite these advances, there are still several risks associated with pharmacological and surgical intervention of obesity and the metabolic syndrome, suggesting that dietary modification may be the safest and most cost-effective option for those who are moderately obese [10-12]. To date, nutritional intervention is still the preferred method of treatment and prevention for obesity and the metabolic syndrome [9,13].
Tea (Camellia sinensis, Theaceae) is the second popular beverage in the world, next to water. The three main types of tea, green, oolong, and black, differ in terms of processing and chemical composition. Green tea is prepared by either steaming or pan-frying tea leaves to inactivate oxidative enzymes. In the preparation of oolong and black tea, the leaves are crushed and allowed to undergo a polyphenol oxidase-mediated oxidation known as fermentation. Many of the putative health benefits of tea are attributed to the high polyphenol content of this beverage . Although all types of tea are rich in polyphenolic compounds, the processing of tea dictates the types and quantities of polyphenols that are found in each specific beverage. Whereas black tea contains oligomeric compounds known as theaflavins and thearubigens, green tea contains mainly monomeric polyphenols known as catechins. A typical brewed green tea beverage (2.5 g green tea in 250 ml hot water) contains about 240 – 320 mg catechins including (−)-epicatechin (EC), (−)-epigallocatechin (EGC), (−)-epicatechin-3-gallate (ECG), and epigallocatechin-3-gallate (EGCG). Small amounts of (+) catechin and (+) gallocatechin are also present . EGCG is the most abundant catechin present in green tea and accounts for approximately 30 – 50% of the catechin content . In addition to the catechin constituents in green tea, caffeine is also present at relatively high amounts . Studies have also indicated that caffeine may play a role in the preventive effects of green tea against cancer, MetS and other disease states [16,17].
Green tea has been reported to have preventive effects against a number of chronic diseases including heart disease, neurodegenerative disease, cancer, and others [18,19]. The potential preventive effects of green tea and EGCG on symptoms of MetS have also been investigated in laboratory, epidemiological and intervention studies [20,21]. In this review, we summarize the laboratory-derived data on the potential effects of green tea as an agent for prevention of obesity and the metabolic syndrome with the aim of critically evaluating the results of these studies and synthesizing phenomenological and mechanistic data. The focus of this review will be on studies conducted in animal models related to MetS and we will also discuss relevant in vitro mechanistic data. For organizational purposes, we have subdivided the review into sections on the individual symptoms of MetS (i.e. obesity, diabetes/insulin resistance, hypertension, hypercholesterolemia, and ORFLD), although given the nature of the models used and the multiple symptoms involved, clear demarcations of sections are somewhat difficult to make.
2. Prevention of obesity by green tea polyphenols
Obesity is associated with increased health-care costs, reduced quality of life, and increase risk for premature death, defined as a body mass index (BMI) or 30 or greater . The Centers of Disease Control and Prevention reported that during the past 20 years there has been dramatic increase in the rate of obesity in the United States and currently more than 60% of US population is overweight or obese . The effects of green tea and green tea polyphenols have been examined in a number of animal models of obesity (Table 1).
Hasegawa et al. reported that oral administration of 130 mg powdered green tea daily to male Zucker rats fed a 50% sucrose diet containing 15% butter resulted in reduction of body weight gain within 2 days. In addition, rats treated with powdered green tea had significantly lowered adipose tissue weight (5 – 9% decrease) and liver weight (11% decrease) . Green tea treatment (2% in the diet) reduced body fat accumulation in Sprague-Dawley rats after 14 days but did not alter body weight gain .
Park et al.  have studied the effects of green tea extract on obesity and hepatic steatosis in leptin-deficient B6.V-Lepob/J (ob/ob) mice. Treatment with 1% green tea extract containing 30% (w/w) total catechins for 6 weeks resulted in decreased body weight gain compared to control mice. Green tea treatment also reduced adipose tissue mass (21% decrease), hepatic lipids (13% decrease), and serum alanine aminotransferase (ALT, 25% decrease) compared to control mice. Immunohistochemical analysis showed that 1% green tea extract treatment decreased hepatic expression of the inflammatory marker, tumor necrosis factor (TNF)-α, in the liver and adipose tissue.
Studies with green tea extract are potentially confounded by the presence of caffeine. In order to determine the relative contribution of the tea polyphenols and caffeine, some investigators have examined the effects of decaffeinated green tea or compared the effects of green tea extract, tea catechins, and caffeine. A recent study compared the effects of supplementation with decaffeinated green tea powder, tea catechins, and heat-treated tea catechins in Sprague-Dawley rats . All three treatments caused significantly reduced final body weight and epididymal, mesenteric and perirenal and retroperitoneal adipose tissue. Richard et al.  likewise studied the effects of decaffeinated green tea in both diet-induced obesity in C57BL/6J mice and genetic obesity in the ob/ob mouse. The results showed that administration of 2% decaffeinated green tea for 6 weeks to ob/ob mice significantly slowed the rate of body weight gain compared to control group, but there was no difference in C57BL/6J mice treated and control group. By contrast, caffeine was shown to play an important role in the effects of green tea in SAMP10 mice, which develop brain atrophy and cognitive dysfunction due to accelerated senescence and are susceptible to high fat diet induced obesity. Treatment with 0.3% green tea catechins and 0.05% caffeine for 12 months improved brain atrophy, brain dysfunction and obesity whereas treatment with catechins alone did not show significant lower body weight and adipose tissue weight .
Many studies have focused on the effects of purified tea catechin preparations or pure EGCG. Supplementation of high-fat fed C57BL/6J mice fed with 0.2 and 0.5% tea catechin was shown to reduce body weight gain, visceral adipose tissue weight (44 – 87% decrease) and liver triglyceride (53 – 75% decrease) [29,30]. Tea catechin treatment also reduced plasma total cholesterol and plasma glucose in non-fasting condition . A study in obese male Sprague-Dawley rats fed high-fat diet found that administration of 0.5% tea catechins for 8 weeks did not significantly lower the body weight or visceral adipose tissue, but did reduce by interscapular brown adipose tissue 15% . Treatment of high-fat fed C57BL/6J mice with 0.32% dietary EGCG for 16 weeks reduced body weight gain by 33 – 41% compared to high fat-fed controls . In addition, the EGCG-treated mice had significantly lower total visceral adipose tissue weight (37% decrease). The same group also found that EGCG treatment for 4 weeks significantly lowered the weight of the mesenteric adipose depot (36% decrease) and tended to decrease body weight (not statistically significant). Sprague-Dawley rats treated with 1% w/w TEAVIGO (90% EGCG) for 1 month showed reduction of subcutaneous adipose tissue (10% decrease), epididymal adipose tissue (5% decrease), and fed state triglyceride (11% decrease) . By contrast Raederstorff et al.  showed that supplementation with 0.25%, 0.5% and 1.0% EGCG had no significant effect on body weight and liver weight in Wistar rats fed a high-fat, high cholesterol diet for 4 weeks, EGCG (1%) did however reduce total plasma cholesterol and non-HDL cholesterol and hepatic total cholesterol concentration by 37%, 55% and 17% respectively compared to control group.
A number of mechanisms have been proposed to explain the anti-obesity effects of green tea. One reported by several groups is related to modulation of dietary lipid absorption by green tea treatment. Yang et al. and Muramastu et al. [35,36] have reported that green tea extract and green tea catechins increase fecal lipid content in high fat-fed rats. Similar findings have been observed in high fat-fed mice. For example, EGCG supplementation (0.32% in the diet) for 16 weeks increased fecal lipid content in high fat-fed mice by 144% compared to high fat controls . Treatment with 0.5% and 1.0% EGCG has also been shown to increase fecal cholesterol excretion and fecal fat excretion in high fat, high cholesterol-fed rats compared to control group 4]. Fecal lipid content was also shown to increase following treatment of ob/ob mice with decaffeinated green tea for six weeks, although the effect was not statistically significant. This may be due to the relatively short intervention time compared to other studies .
Green tea extract and tea catechins have been reported to inhibit pancreatic lipase. An in vitro under gastric and duodenal conditions showed that fat digestion was significantly inhibited by inclusion of 60 mg EGCG/g triolein substrate, and this effect was related to the changes in lipid emulsification in gastric or duodenal media . A recent study showed that EGCG at the achievable by typical daily intake changed the physiochemical properties of a lipid emulsion by increasing its particle size and reducing the surface area ; such changes decreased the ability of pancreatic lipase to digest dietary fats . Ikeda et al.  demonstrated that a mixture of catechins high in EGCG and ECG inhibited pancreatic lipase in vitro and suppressed postprandial serum triglyceride in vivo in a dose-dependent manner. It has been proposed that the hydroxyl moieties of EGCG interact with the hydrophilic head group of phosphatidylcholine at the exterior of a lipid emulsion by forming hydrogen bonds. These interactions may lead to formation of cross-links followed by coalescence of the emulsion droplets .
Modulation of lipid metabolism in liver and/or adipose tissue has also been suggested as a potential mechanism by which prevents obesity. Studies have focused on the effect of green tea or EGCG on expression and activity of enzymes related to fatty acid synthesis or fatty acid oxidation. Supplementation of 1% tea catechin and heat-treated tea catechin in Sprague-Dawley rats for 23 days reduced activities of fatty acid synthase (FAS) and malic enzyme in the liver significantly where there was a tendency of reduction of glucose-6-phosphate dehydrogenase (G6PDH), carintine palmitoyltransferase (CPT) and acyl coA oxidase (ACO) activities . Klaus et al.  also reported that dietary supplementation of 0.5% and 1% EGCG reduced leptin expression of epididymal adipose tissue and reduced expression of SCD-1, malic enzyme, and glucokinase in the liver. EGCG supplementation was shown to significantly decrease FAS, glycerol-3-phosphate acyltransferase, sterol-coenzyme A desaturase (SCD-1) mRNA expressions in adipose tissue compared to high fat-fed mice [33,41]. These enzymes are related to fatty acid synthesis such as SCD-1 is the rate-limiting enzyme in the synthesis of monounsaturated fatty acids. Reduction of fatty acid synthesis is expected to leadto reduced triglyceride deposition in the liver and adipose tissue.
Inhibition of FAS and G6PDH by green tea and EGCG have also been observed in vitro. Yeh et al.  showed that the expression of fatty acid synthase mRNA in malignant human breast carcinoma MCF-7 cells was suppressed by the addition of the green tea (60 - 120 μg/mL) and EGCG (76% decrease at 30 μM). EGCG suppressed FAS induction by epidermal growth factor (EGF) by inhibiting the phosphatidylinositol 3-kinase (PI3K)/Akt – mediated signaling. Kao et al.  found that EGCG inhibited glycerol-3-phosphate dehydrogenase (GPDH) with IC50 value of 20 μM in a cell-free system. Also they revealed that EGCG was a noncompetitor of GPDH substrates, NADH and dihydroxyacetone phosphate (DHAP) with respective inhibition constants (Ki) of 18 and 31 μM. In both cases, the concentrations of EGCG are quite high.
Many studies have examined the effects of tea catechin or EGCG on β-oxidation. The supplementation with 0.5% tea catechin in C57BL/6J mice significantly increased β- oxidation activity in the liver, and the increases in mRNA levels of ACO and medium chain acyl-CoA dehydrogenase (MCAD) in the liver were observed [29,30]. Interestingly, no change in FAS expression was observed. Other recent studies [25,44] have shown that EGCG can modify gene expression in epididymal white adipose tissue of treated mice. The mRNA levels of adipogenic genes related to adipocyte differentiation such as peroxisome proliferator-activated receptor (PPAR)-γ, CCAAT enhancer-binding protein-α (C/EBP-α), sterol regulatory element-binding protein-1c (SREBP-1c), adipocyte fatty acid-binding protein (aP2), lipoprotein lipase (LPL), fatty acid synthase (FAS), and stearoyl-CoA desaturase (SCD-1) were significantly decreased. The similar results of gene expression related to adipocyte differentiation (SREBP-1c, FAS, and SCD-1) were found in the liver . Moreover, the increase of mRNA levels of genes related to lipolysis, β-oxidation and thermogenesis which are CPT-1, uncoupling protein (UCP)2, hormone sensitive lipase (HSL) and adipose triglyceride lipase, were observed . The study of Nomura et al.  have shown that tea catechin intake in the context of normal fat diet (12% calories from fat) significantly increased the UCP1 mRNA expression in brown adipose tissue. Similar effects have also been observed in the content of a high fat diet. UCP1 plays a role in thermogenesis in brown adipose tissue and may help explain the reduction of fat weight following treatment with tea catechins.
A recent study by Murase et al.  studied the effects of EGCG in BALB/c mice and the results showed that oral administration of EGCG (200 mg/kg BW) induced an increase in AMPKα activity in the liver. Respiratory quotient values tended to decrease as determined by indirect calorimetry and it showed significant increase in fat oxidation which suggested that EGCG increased fatty acid oxidation although no change in body their body weight was observed. In vitro study, the same group reported that EGCG not only induced the increase of AMPKα but that a gallocatechin moiety or a galloyl residue, acted as AMPK activators.