Weight Control and Slimming Ingredients in Food Technology (Cho/Weight Control and Slimming Ingredients in Food Technology) || Mechanisms of (−)-Epigallocatechin-3-Gallate for Antiobesity

P1: SFK/UKS P2: SFKc11 BLBS044-Cho October 15, 2009 8:11 Printer Name: Yet to Come

CHAPTER 11

Mechanisms of (−)-Epigallocatechin-3-Gallatefor Antiobesity

Hyun-Seuk Moon, PhD, Mohammed Akbar, PhD, Cheol-HeuiYun, PhD, and Chong-Su Cho, PhD

Abstract

It has long been recognized that obesity is major risk factor for numbers of dis-orders including diabetes, hypertension, and heart diseases. For these, adipocytesplay a central role in maintaining lipid homeostasis and energy balance in ver-tebrates by storing triacylglycerols (TGs) and releasing free fatty acids (FFAs)in response to changes in energy demands. Last few years, numerous studies re-garding green tea catechins (GTCs) are reported to exhibit a variety of biologicalactivities including cancer prevention and cardiovascular health. Furthermore,the obesity-preventive effects of green tea and its main constituent especially(−)-epigallocatechin-3-gallate (EGCG) are widely supported by results from epi-demiological, cell culture, animal, and clinical studies. In this review, the bio-logical activities and multiple mechanisms of EGCG in vitro and in vivo studiesincluding animal models and clinical observations are explained.

Introduction

Adipocytes and Obesity

It is well known that adipocytes play a critical role in maintaining lipidhomeostasis and energy balance by either storing triacylglycerols (TGs) or

177Weight Control and Slimming Ingredients in Food Technology Susan S. Cho© 2010 Blackwell Publishing. ISBN: 978-0-813-81323-3


178 Functional Components

releasing free fatty acids (FFAs) dependent on changes of energy demands(Fruhbeck et al., 2001). In the industrialized countries, obesity becomes amajor risk factor for numbers of disorders such as diabetes, hypertension,and heart disease (Farmer and Auwerx, 2004; Kelly and Goodpaster, 2001;Lee et al., 2005; Lewis et al., 2002). Also, several lines of evidence havesuggested that TG accumulation in skeletal muscles and pancreatic isletsis causally related to the insulin resistance together with pancreatic β-celldysfunction in obese patients (Kelly and Goodpaster, 2001; Lewis et al.,2002). The development of obesity can be characterized by an increasednumber of fat cells and the contents of lipids due to the processes socalled mitogenesis and differentiation, which are regulated by genetic,endocrine, metabolic, neurological, pharmacological, environmental, andnutritional factors (Farmer and Auwerx, 2004; Lewis et al., 2002; Ungerand Zhou, 2001). Accordingly, an understanding of the mechanism bywhich particular nutrients affect the mitogenesis of preadipocytes andtheir differentiation to adipocytes would help to understand, and thereforeprevent the initiation and progression of obesity and its associated diseases(Unger and Zhou, 2001).

Green Tea

After water tea is the second most widely consumed beverages in theworld, and its origins date back thousands of years (Rusznyak and Szent-Gyorgyi, 1936). Green tea, prepared by drying fresh tea leaves, contains anumber of bioactive components, including polyphenols, caffeine, aminoacids, and other trace compounds such as lipids and vitamins (Safe, 2001).It has been suggested that the health-promoting effects of green tea aremainly attributed to its polyphenol content (Roberts, 1953; Rusznyakand Szent-Gyorgyi, 1936; Safe, 2001). In fact, green tea is a rich sourceof polyphenols, especially flavanols and flavonols, which represent ap-proximately 30% of dry weight of its fresh leaf (Ahmad and Mukhtar,1999; Lin et al., 1999; Roberts, 1953; Safe, 2001). Catechins are the pre-dominant form of the flavanols and mainly comprised epigallocatechingallate (EGCG), epigallocatechin (EGC), epicatechin gallate (ECG), andepicatechin (EC) (Ahmad and Mukhtar, 1999; Roberts, 1953). Not onlythey have unique chemical structures (Fig.11.1) and are major ingredientsof unfermented tea (Hung et al., 2005) but they have been also foundto possess widespread biological functions and health benefits (Chunget al., 2003; Kong et al., 2000; Lambert and Yang, 2003; Mukhtar andAhmad, 2000; Riemersma et al., 2001). Recently, it is becoming clear that


Mechanisms of (−)-Epigallocatechin-3-Gallate 179

OH

OH

OH

OH

OH

OH

G=galloyl:

R1

R1 R2 g/mol

OR2

HO

A

O7

53

2

4´

5´

CC

O

(−)Epicatechin (EC)(−)Epigallocatechin (EGC)(−)Epicatechin-3-gallate (ECG)(−)Epigallocatechin-3-gallate (EGCG)

HOH

HOH

HHGG

290306442458

B

Figure 11.1. Structures of four major green tea catechins. Differences amongthese catechins occur in the number of hydroxyl groups, the presence of a galloylgroup, and the molecular weight (Hung et al., 2005; reprinted with permission).

many of the aforementioned beneficial effects of green tea were attributedto its most abundant catechin, EGCG (Ahmad and Mukhtar, 1999; Linet al., 1999; Roberts, 1953).

Indeed, it has been shown that EGCG lowers the incidence of variouscancers (Ahmad and Mukhtar, 1999; Lin et al., 1999; Mitscher et al.,1997; Roberts, 1953), collagen-induced arthritis (Yang and Wang, 1993),oxidative stress-induced neurodegenerative disease (Haqqi et al., 1999),and streptozotocin-induced diabetes (Mendel and Youdim, 2004). Also, ithas been clearly demonstrated that EGCG or EGCG-containing green teaextract reduces food uptake, lipid absorption, and blood TGs, cholesterol,and leptin levels, as well as stimulating energy expenditure, fat oxidation,high-density lipoprotein (HDL) levels, and fecal lipid excretion (Safe,2001; Song et al., 2003).

The Aim of This Review

During the last decades, the obesity-preventive effects of green tea andits main compound EGCG are widely supported by results from epidemi-ological, preclinical, and clinical studies. This review focuses on in vitro



and in vivo studies investigating the antiobesity effects of green tea orisolated green tea components and attempts to explore the underlyingmechanisms. The possible relevance of each of the proposed mechanismon human obesity prevention is also discussed. The mechanisms for an-tiobesity discussed in this review may possibly be utilized in the furtherresearch and therapeutic treatment of patients with obesity and its relateddisease.

Antiobesity Mechanisms of EGCG

Antiadipogenic Effect of EGCG via ExtracellularSignal-Regulated Kinase (ERK)-DependentSignaling Pathway

Mitogen-activated protein kinases (MAPKs) are serine/threonine-specific protein kinases composed of extracellular signal-related kinases(ERK) and c-Jun-N-terminal kinases (JNK) and p38 that respond toextracellular stimuli (e.g., mitogens) and regulate various cellular ac-tivities, such as gene expression, mitosis, differentiation, and cell sur-vival/apoptosis. The activation of MAPK results in regulation of geneexpression by phosphorylation of a variety of transcription factors andmodification of their transcriptional efficiencies in a variety of cell types(Pearson et al., 2001). Importantly, in adipocytes, both ERK and JNKcan phosphorylate peroxisome proliferator-activated receptor γ (PPARγ),which results in repression of its transcriptional activation potentialand adipogenesis (Ahmad and Mukhtar, 1999). In relation to this ac-tion, EGCG has been proposed to serve as signal elements in sev-eral types of cells where EGCG may regulate cell growth (Ahmadand Mukhtar, 1999; Yang and Wang, 1993) and may modulate the mi-togenic and adipogenic signalings of IGF-I in 3T3-L1 preadipocytes(Levites et al., 2002). In addition, the antiadipogenic effect of EGCGappears to be important not only in reducing adipocyte differentiation(hypertrophy) but also in inhibiting adipocyte proliferation (hyperplasia),suggesting that ERK1/2, enzymes that involved in the control of cellcycle, is required for these inhibitory effects (Hung et al., 2005). Sup-porting this hypothesis, Hung et al. (2005) reported that EGCG induceda decrease in phosphorylated ERK1/2 in 3T3-L1 preadipocytes but didnot alter the total levels of MEK1, ERK1/2, p38, phospho-p38, JNK,or phospho-JNK (Fig.11.2), suggesting that EGCG acts specifically on aphosphorylation of the ERK1/2. This contention is also partially supported



Figure 11.2. Effects of EGCG on ERK1/2, phospho-ERK1/2 and MEK1 in3T3-L1 preadipocytes (day 3). (a) Time-dependent effect of EGCG at 50 µMwas observed. (b) Dose-dependent effect of EGCG was observed after 4 hours oftreatment. (c) EGCG at 50 µM altered MEK1 activity as indicated by decreasedphospho-ERK1/2, which was dependent on the growth phases of cells after4 hours of treatment. Day 1, the day when cells were plated; latent, day 3;log-phase, day 5 (confluent). The kinases were measured by Western blot analy-sis and then expressed after normalization to β-actin. Data are expressed as mean± SE from triplicate determinations. In some data, SE bars are too small to beseen. * indicates p < 0.05 when compared to the control (Hung et al., 2005;reprinted with permission).



by the fact that exposure (24 or 48 hours) to EGCG induced a decrease inthe phosphorylated ERK1/2 of preadipocytes without altering total levelsof MEK1 or ERK1/2 proteins (Levites et al., 2002).

Antiadipogenic Effect of EGCG via Resistin(RSTN)-Modulated Adipogenesis

Adipokines, mainly produced by adipocytes, are active participantsin the regulation of inflammation (Arner, 2005). Among them, resistin(RSTN), known as an adipocyte-specific secretory factor (ADSF), is im-plicated to modulate insulin resistance in rodents (Adeghate, 2004). In-terestingly, RSTN is expressed in white adipose tissue in mouse, butmainly in leukocytes in human. Steppan et al. reported that RSTN hasan inhibitory effect on insulin-stimulated glucose uptake in differentiated3T3-L1 adipocytes (Steppan et al., 2001). Recent study suggested that in-tracellular RSTN protein significantly decreased in the presence of 100 µMEGCG 3 hours after treatment, whereas the release of the RSTN proteinhas no significant change (Liu et al., 2006), suggesting that EGCG maymodulate the distribution of RSTN protein.

Antiadipogenic Effect of EGCGvia Cyclin-Dependent Kinase 2(CDK 2)-Dependent Signaling Pathway

It has been shown that EGCG downregulated adipocyte differentiationthrough the CDK2 signaling pathway (Hung et al., 2005). These resultssuggested that the antimitogenic effect of EGCG on 3T3-L1 preadipocytesis dependent on the ERK MAPK and cyclin-dependent kinase 2 (CDK2)pathways and is likely mediated through decreases in their activities.Also, Wu et al. reported that the apoptotic effect of EGCG on 3T3-L1preadipocytes is dependent on the Cdk2 and caspase-3 pathways and islikely mediated through alterations in their activities (Wu et al., 2005),suggesting that decreases in Cdk2 activity by EGCG may be due to itseffect on this particular member of the CKI family. However, there arevery limited studies between EGCG and CDK. In vivo study suggested thatCDK2 activity can be regulated by the association of stimulatory proteinssuch as cyclin E (Morgan, 1995). Hence, more investigations are neededto clarify whether the production of cyclin E protein and its association



with CDK2 can be altered by EGCG and thereafter resulting decreases inCDK2 activity.

Antiadipogenic Effect of EGCG via Activationof AMP-Activated Protein Kinase (AMPK)

AMPK is known to play an important role in energy homeostasis bycoordinating number of effectors responses in ATP-depleting metabolicstates such as ischemia/reperfusion, hypoxia, heat shock, oxidative stress,and exercise (Kemp et al., 2003; Morgan, 1995). Moreover, AMPK pro-motes oxidation of fatty acid and inhibits lipid synthesis in cells throughphosphorylation and inhibition of acetyl-CoA carboxylase (ACC) activity(Jaleel et al., 2006; Shaw et al., 2004; Xie et al., 2006). The persistent ac-tivation of AMPK has been shown to be linked to p53-dependent cellularsenescence, suggesting its role as an intrinsic regulator of the cell cycle(Jones et al., 2005). Moreover, AMPK cascades have emerged as noveltargets for the treatment of obesity and type II diabetes (Luo et al., 2005;Meisse et al., 2002; Song et al., 2002). Hwang et al. (2005) suggestedthat several naturally occurring compounds including EGCG or capsaicinhave potential antiobesity effects by activation of AMPK and inhibition ofadipocyte differentiation in 3T3-L1 cells. This result indicated that AMPKactivation is necessary for the inhibition of adipocyte differentiation byEGCG and capsaicin. Furthermore, Collins et al. reported that EGCGsuppresses hepatic gluconeogenesis through ROS, CaMKK, and AMPK(Collins et al., 2007). Hence, the mechanism that affects AMPK regulationafter EGCG treatment could be a promising target for the development ofstrategies to treat obesity.

Antiadipogenic Effect of EGCG via Regulationof Reactive Oxygen Species (ROS)

Generally, ROS has been suggested as upstream molecules of AMPK-activated signals (Collins et al., 2007; Giakoustidis et al., 2008; Kemp etal., 2003; Meng et al., 2008; Qanungo et al., 2005; Yao et al., 2008). Infact, Hwang et al. reported that genistein inhibits adipocyte differentiationand the induction of adipocyte apoptosis through the activation of AMPKparalleled with the generation of ROS, and this effect was similar to thatof EGCG treatment (Hwang et al., 2005). Therefore, one of the AMPKactivation mechanisms was suspected to be ROS, which was supported by



reports that various therapeutic effects in naturally occurring compoundswere mediated by the release of ROS (Qanungo et al., 2005). Hwang et al.have shown that genistein induced ROS generation significantly, which ledto AMPK activation, and these effects were abolished by its inhibitor, NAC(5 mM) treatment (Hwang et al., 2005). These results indicate that ROS isnecessary for AMPK activation in the inhibitory process of adipocyte dif-ferentiation by phytochemicals in 3T3-L1 cells. Recent study also showedthat EGCG at relatively low and nontoxic concentration (equal or less than1 µM) inhibited glucose production by hepatic gluconeogenesis mediatedby AMPK activation through Ca2+/calmodulin-dependent protein kinasekinase (CaMKK) and ROS (Giakoustidis et al., 2008). Meng et al. investi-gated EGCG for its antiaging effect on human diploid fibroblasts (HDF).In this study, HDF treated with EGCG at 25 and 50 µM for 24 hours dra-matically increased catalase, superoxide dismutase (SOD)1, SOD2, andglutathione peroxidase gene expressions and their enzyme activities. Fur-thermore, these activities appeared to be necessary to protect HDF againsthydrogen peroxide (H2O2)-induced oxidative damage, accompanied withdecreased accumulation of intracellular ROS and well-maintained mito-chondrial integrity (Meng et al., 2008).

Antiadipogenic Effect of Green Tea via Inhibitionof Lipogenic Enzymes

GTCs are known to possess antilipogenic activity (Kao et al., 2006).They can inhibit the activity and/or expression of lipogenic enzymes,such as ACC, fatty acid synthase (FAS), malic enzyme (ME), glucose-6-phosphate dehydrogenase (G6PDH), glyceol-3-phosphate dehydrogenase(G3PDH), and stearoyl-CoA desaturase-1 (SCD-1) (Table 11.1) (Ahmadand Mukhtar, 1999; Crespy and Williamson, 2004; Kao et al., 2006; Linet al., 1999).

ACC involves the rate-limiting step in fatty acid synthesis for catalyzingthe conversion of acetyl-CoA to malonyl-CoA (Kimura et al., 1983). WhenECG or EGCG from green tea was incubated with rat liver ACC, they (withKi of 310 µM) inhibited the activity of ACC (Kimura et al., 1983). How-ever, such activity was not observed when (+)-catechin, EC or EGC, wasused. A recent report also showed that EGCG supplementation downregu-lates ACC mRNA expression in obese mice (Ahmad and Mukhtar, 1999).It has also been reported that when EGCG was incubated with chickenFAS, the second enzyme to catalyze the conversion of malonyl-CoA tofatty acyl-CoA, it inhibited FAS activity with an IC50 of 52 µM (Wang



Table 11.1. EGCG inhibition of lipid-related enzymes in cell-free systemsa

Enzymes IC50 (µM)

Lipogenic enzymesACC 310Aromatase 60FAS 52Lanosterol 14α-demethylase >100Oxidosqualene: lanosterol cyclase >100Squalene epoxidase 0.7

Lipolytic enzymesGLb 10PL 0.34–11

OxidoreductaseGlycyrhizin-binding lipoxygenase 10Lipoxygenase 10Type 1 5α-reductase 15Type 2 5α-reductase 74

OthersCOMT 0.2

Sources: Kao et al., 2006; reprinted with permission.aActivity and expression of some enzymes that have been found to be affected by tea catechinsin cell or animal systems include ACC, FAS, ME, G6PDH, G3PDH, SCD1, acyl-CoA oxidase,medium-chain acyl CoA dehydrogenase, UCP2, UCP3, fatty acid translocase, carnitinepalmitoyltransferase, and HSL.bThe unit is expressed as milligrams of green tea extract per gram of tributyrin substrate.

and Tian, 2001). Generally, inhibitory activity of FAS by EGCG dependson reversible fast-binding inhibition and irreversible slow-binding inacti-vation (Wang and Tian, 2001). Because FAS shows high levels of activityin LNCaP human prostate cancer cells, EGCG treatment at 100 µM for24 hours inhibited 52% FAS activity (Brusselmans et al., 2003). In ad-dition, EGCG is reported to suppress FAS mRNA and protein levels inMCF-7 breast cancer cells suggested that EGCG signaling may be in-volved in the downregulation of the EGF receptor and its downstream Aktand Sp-1 proteins (Yeh et al., 2003). Moreover, a decrease in the expressionof hepatic ME and G6PDH, which generate NADPH for fatty acid bio-genesis, has also been observed in obese mice when treated with EGCG(Ahmad and Mukhtar, 1999). Furthermore, the activity and expressionof G3PDH involving a step in TG biosynthesis are decreased by EGCGtreatment (Mochizuki and Hasegawa, 2004). Also, it was found that geneexpression of SCD1, utilized for the synthesis of monounsaturated fatty



acids by liver and adipose tissue, was suppressed in EGCG-treated obesemice (Ahmad and Mukhtar, 1999). Overall, green tea, EGCG in particu-lar, appears to reduce fatty acid and TG synthesis by inhibiting lipogenicenzymes, and this may explain its hypolipidic effects.

Antiadipogenic Effect of Green Tea viaDownregulation of Adipocyte MarkerProteins and Its Target Genes

Generally, the enforced expression of PPARγ and C/EBPα stimulatesadipogenesis in NIH 3T3 fibroblasts, suggesting the essential role of thesetranscription factors in regulating adipogenesis (Chu et al., 1995; Dalei andLazar, 1997). In fact, PPARγ2 and C/EBPα are found almost exclusivelyin the adipose tissue and have been linked to the adipocyte differentia-tion (Hwang et al., 1997), which could play a crucial role both in theinduction of adipose-specific genes and in the manifestation of the ma-ture adipose phenotype. Furthermore, the combined expression of PPARγ

and C/EBPα has synergistic effects in promoting fat cell conversion inmyoblasts (Brown et al., 2003; Moon et al., 2006), indicating that theyare very important for fat accumulation. Also, these transcription factorscoordinate the expression of genes involved in creating and maintainingthe adipocyte phenotype, including aP2 (Chu et al., 1995). The aP2, amember of intracellular lipid binding protein family, is involved in the for-mation of atherosclerosis predominantly through the direct modificationof cholesterol trafficking and inflammatory responses in the macrophages(Chu et al., 1995; Dalei and Lazar, 1997). By contrast, it was demonstratedthat EGCG significantly downregulated the expression of adipocyte makergenes during adipocyte differentiation (Yang and Wang, 1993), indicatingthat the negative impact of EGCG on adipogenesis was accompanied bythe reduction of PPARγ2 protein in 3T3-L1 cells coincide with the at-tenuation of C/EBPα expression. Because PPARγ is one of the key tran-scription factors in the induction of adipogenesis and lipid accumulation(Brown et al., 2003; Moon et al., 2006), EGCG-induced downregulationof PPARγ expression is likely to suppress the lipid accumulation andadipocyte differentiation (Haqqi et al., 1999; Kao et al., 2000; Mendeland Youdim, 2004; Song et al., 2003). On the other hand, TG hydrolysisproportionally released glycerol and FFA from adipocytes, and the glyc-erol release caused the lipolysis in the adipocytes (Moussalli et al., 1986).Certain natural compounds such as conjugated linoleic acid (CLA) andforskolin-induced lipolysis in adipocyte models (Wolfram et al., 2006b).



In fact, we previously reported that CLA had an antiadipogenic effectand induced lipolysis in 3T3-L1 cells (Moon et al., 2006). It is to notefrom another study that GTCs strongly reduced adipocyte differentiationbut did not induce lipolysis (Wolfram et al., 2006a), indicating that theantiadipogenic effects of EGCG have no direct relation with changes oflipolysis.

Insulin-Potentiating Activity by Green Tea

In addition to the antiadipogenic effects of EGCG on adipocyte markerprotein expression, Wu et al. reported that, after 12 weeks of green teasupplementation, the fasting plasma glucose and insulin levels in the greentea group were significantly lower than those in the control group (Wuet al., 2004).

As shown in Fig. 11.3, during the 2 hours following glucose ingestion,no difference was seen in the plasma glucose levels between the twogroups. However, the plasma insulin levels of the group fed with greentea at all time points were significantly (p < 0.05) lower than those in thecontrol group. In fact, the AUCs for plasma glucose and insulin were 336

250

200

150

100

50

0

(a) (b)ControlGreen tea

Pla

sma

gluc

ose

(mg/

dL)

Pla

sma

insu

lin (

µU/m

L)

0 30 60 90 120

Time (min)

150

50

40

30

20

10

00 30 60

*****

*

90 120

Time (min)

150

Figure 11.3. Changes in plasma levels of glucose (a) and insulin (b) in rats inresponse to an oral glucose tolerance test (2 g of glucose/kg of BW) performedafter 12 weeks with or without green tea supplementation. Values are shown asthe mean ± SD. * indicates p < 0.05 when compared to the control group (Wuet al., 2004; reprinted with permission).



± 11 mg h/dL and 38 ± 10 µU h/mL, respectively, in the group fed withgreen tea, whereas 346 ± 13 mg h/dL and 60 ± 18 µU h/mL, respectively,in the control group. No significant difference was found between thetwo groups in the AUC for plasma glucose (p = 0.260); however, theAUC for insulin in the group fed with green tea was significantly lower(p = 0.004) than the control group, demonstrating that the green teacauses increase of insulin sensitivity. These results indicated that greentea supplementation in the form of regular tea infusion could increaseinsulin sensitivity by increasing the glucose uptake. It is believed that thebeneficial effects of green tea are due to the polyphenols, the principalactive ingredients. It provides the protection against oxidative damageand antibacterial, antiviral, anticarcinogenic, and antimutagenic activities;however, it may also increase insulin activity (Wu et al., 2004). Severalcompounds found in green tea were also shown to enhance insulin activity,for instance, EGCG as the greatest activity, followed by ECG, tannins, andtheaflavins (Anderson and Polansky, 2002; Carobbio et al., 2004; Wu et al.,2004). Supporting these results, Anderson et al. reported that the insulin-potentiating activity in green and oolong tea was mainly due to EGCG(Table 11.2) (Anderson and Polansky, 2002). These data demonstratedthat the increased insulin together with its activity of the tea leaves ispredominantly due to the presence of the active ingredient EGCG. Insulinsecretion by pancreatic β cells is stimulated by glucose, amino acids, andother metabolic fuels (Carobbio et al., 2004).

Li et al. reported that EGCG does not affect glucose-stimulated insulinsecretion under high-energy conditions when glutamate dehydrogenase(GDH) is fully inhibited. They also showed that EGCG acts in an al-losteric manner independent of their antioxidant activity and that the β-cell

Table 11.2. Insulin activity ratios of fractions from Oolong teaa

Fraction Time(minutes)

Insulin ActivityRatio

Fraction Time(minutes)

Insulin ActivityRatio

2.5–6 1.5 38–44 1.16–13 1.2 44–47 0.9

13–20 1.3 47–52 1.320–23 4.5 52–60 1.423–28 1.0 60–68 1.3

Sources: Anderson et al., 2002; reprinted with permission.aFractions were collected as described for the chromatogram. Individual fractions were concentratedby rotoevaporation to 0.5 mL and diluted fivefold in water prior to assay.



stimulatory effects are directly correlated with glutamine oxidation(Li et al., 2006).

Epidemiological Observation of Green Teaand Clinical Studies

Although some epidemiological studies have failed to provide clear-cut evidence for a link between tea consumption and body weight (Konoet al., 1996), several studies have shown that tea intake is associatedwith decreased serum concentrations of total cholesterol and lipoprotein.For example, Tokunaga et al. reported that green tea consumption wasinversely associated with serum levels of total cholesterol and LDL, butnot with body weight index, HDL, and TG (Tokunaga et al., 2002). Inanother study with men over 40 years of age, higher levels of greentea consumption were associated with a proportional increase of HDLcoincide with a proportional decrease of LDL and serum concentrationsof total cholesterol and TG, but not with the body weight index (Imai andNakachi, 1995).

In a recent clinical study, green tea extract containing 25% EGCGexerted reduction of body weight (4.6%) and waist circumference (4.5%)in moderately obese patients 3 months after treatment (Chantre and Lairon,2002). Also, Nagao et al. (2005) reported that the subjects who ingestedone bottle of oolong tea containing 690 mg GTCs/day for 12 weeks hada lower body weight, body weight index, waist circumference, body fatmass, and subcutaneous fat area than did the subjects who ingested onebottle of oolong tea containing 22 mg catechins/day (Table 11.3). Theseearly studies indicated the beneficial effects of GTCs to reduce bodyweight.

Also, Nakagawa et al. clearly demonstrated that when 18 healthyJapanese men were given a green tea extract containing 254 mg, theirplasma level of EGCG reached 0.27 nM in 1 hour after administration,while plasma phospholipids, total cholesterol, and TG did not change.However, the plasma phatidycholine hydroperoxide level decreased from74 pM in controls compared to 45 pM in EGCG-treated subjects, suggest-ing that tea catechins are as effective as antioxidants (Nakagawa et al.,1999).

It is to note that there are controversial observations on the regulationof energy expenditure and fat oxidation by green tea in human. In fact,according to a respiratory chamber study, ten healthy men had a greentea extract that contains 50 mg caffeine and 90 mg EGCG at breakfast,


Tab

le11

.3.

Cha

nges

inan

thro

pom

etri

cva

riab

les

and

body

com

posi

tion

afte

rco

nsum

ptio

nof

eith

erco

ntro

lor

high

-cat

echi

nbe

vera

ges

for

12w

eeks

a

Init

ial

Four

Wee

ksE

ight

Wee

ksTw

elve

Wee

ksC

hang

eat

Twel

veW

eeks

Wei

ght

(kg)

b,c

Con

trol

grou

p73

.8±

1.3

72.9

±1.

372

.7±

1.4

72.5

±1.

4−1

.3±

0.3

GT

Egr

oup

73.9

±1.

872

.6±

1.7

72.2

±1.

771

.5±

1.7

−2.4

±0.

5B

MI

(kg/

m2 )b

,c

Con

trol

grou

p25

.0±

0.4

24.7

±0.

424

.6±

0.4

24.6

±0.

4−0

.4±

0.1

GT

Egr

oup

24.9

±0.

424

.4±

0.4

24.3

±0.

424

.1±

0.4

−0.8

±0.

2W

aist

(cm

)b–d

Con

trol

grou

p87

.8±

1.1

86.7

±1.

186

.6±

1.1

86.2

±1.

2−1

.6±

0.4

GT

Egr

oup

87.9

±1.

486

.6±

1.4

85.5

±1.

384

.5±

1.3

−3.4

±0.

5H

ip(c

m)b

Con

trol

grou

p97

.0±

0.8

95.9

±0.

795

.8±

0.8

95.8

±0.

8−1

.1±

0.3

GT

Egr

oup

97.4

±0.

997

.0±

0.9

96.0

±1.

196

.1±

1.1

−1.3

±0.

3B

ody

fat

mas

s(k

g)b

,c

Con

trol

grou

p19

.5±

1.0

18.8

±0.

918

.8±

1.0

18.8

±1.

1−0

.7±

0.3

GT

Egr

oup

19.7

±0.

819

.2±

0.9

18.0

±0.

918

.3±

0.9

−1.4

±0.

3L

ean

body

mas

s(k

g)b

Con

trol

grou

p54

.3±

0.7

54.1

±0.

753

.9±

0.7

53.7

±0.

7−0

.6±

0.3

GT

Egr

oup

54.2

±1.

153

.4±

1.0

54.1

±1.

153

.2±

1.0

−1.0

±0.

4

190


Skin

fold

thic

knes

s(m

m)b

,e

Con

trol

grou

p27

.0±

1.5

25.3

±1.

326

.2±

1.5

25.7

±1.

4−1

.3±

0.7

GT

Egr

oup

27.9

±1.

826

.3±

1.6

25.9

±1.

824

.6±

1.5

−3.3

±0.

7T

FA(c

m2 )b,

f

Con

trol

grou

p26

1.0

±12

.725

4.2

±13

.124

6.4

±12

.725

4.3

±13

.6−6

.7±

5.8

GT

Egr

oup

258.

4±

11.0

246.

3±

11.2

232.

1±

9.9

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lunch, and dinner (Dulloo et al., 1999). The results showed that EGCG-containing green tea extracts that contain caffeine are more potent thancaffeine alone at stimulating 24-hour energy expenditure and fat oxidationand urinary norepinephrine excretion. However, in another study involv-ing 104 overweight and moderately obese male and female subjects, agesof 18–60 years and BMI of 25–35 kg/m2, the level of green tea extractsthat contained caffeine (104 mg/day) and EGCG (323 mg/day) were givenfor 13 weeks was not associated with weight maintenance after a 7.5%body weight loss in very low energy diet subjects (Kovacs et al., 2004).This study also showed that habitual caffeine consumption affected weightmaintenance in the green tea treatment. In addition, these clinical obser-vations indicated that long-term, but not short-term, oral consumption ofgreen tea appeared to reduce the body weight and/or fat.

The difference in regulating body weight from these studies may beattributable to the protocols employed, the purity of green tea extracts, theperiod of administration, the percentage of the caffeine, and the physio-logical condition of the subjects.

Summary and Future Direction

Obesity is associated with high blood cholesterol and a high risk fordeveloping diabetes and cardiovascular diseases. Therefore, the manage-ment of body weight and obesity is increasingly recognized as a key factorto maintain healthy cholesterol profiles and to reduce cardiovascular risk.Several drugs are tested and used to treat obese-related metabolic diseasesin association with the possibility of preventing body fat accumulation.Increasing interest in the health benefits of tea has led to the additionof tea extracts in dietary supplements and functional foods among thesesubstances of interest. Especially, EGCG is known to have a beneficial ef-fect on human health that reduced adipocyte differentiation and decreasedTG levels. However, epidemiologic evidence regarding the effects of teaconsumption on obesity-related disease is conflicting. This is an importantarea for future investigations, as it would provide further insight on precisemechanism of EGCG during adipogenesis in the patients. Although morestudies are required to examine the effects and mechanisms of EGCG inanimals and humans, the antiadipogenic effect of EGCG on adipocyte dif-ferentiation seems sounding and promising therapeutic treatment againstobesity. Also, the various mechanisms discussed in this review could beutilized in the treatment of obesity using EGCG.



Acknowledgments

We are grateful to Dr. Dehua Cao at LMS/NIAAA/NIH for providingthe information of green tea.

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Weight Control and Slimming Ingredients in Food Technology (Cho/Weight Control and Slimming Ingredients in Food Technology) || Mechanisms of (−)-Epigallocatechin-3-Gallate for Antiobesity