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Efficacy of a green tea extract rich in catechin polyphenols andcaffeine in increasing 24-h energy expenditure and fat oxidationin humans1–3 Abdul G Dulloo, Claudette Duret, Dorothée Rohrer, Lucien Girardier, Nouri Mensi, Marc Fathi, Philippe Chantre,and Jacques Vandermander ABSTRACT
context, there has been renewed interest in the potential thermo- Background: Current interest in the role of functional foods in
genic effects of many compounds extracted from plants (eg, caf- weight control has focused on plant ingredients capable of inter- feine from coffee and tea, ephedrine from ephedra, and capsaicin fering with the sympathoadrenal system.
from pungent spices), largely because of their potential to modu- Objective: We investigated whether a green tea extract, by
late catecholamine release and activity (4) . For example, cap- virtue of its high content of caffeine and catechin polyphenols, saicin-rich foods (eg, chili peppers and red peppers) have been could increase 24-h energy expenditure (EE) and fat oxidation shown to stimulate fat oxidation and thermogenesis in humans (5, 6), and caffeine in relatively small amounts can potentiate ther- Design: Twenty-four–hour EE, the respiratory quotient (RQ), and
mogenesis induced by sympathetic stimuli, whether in response to the urinary excretion of nitrogen and catecholamines were meas- cold, moderate exercise, or sympathomimetic drugs like ephedrine ured in a respiratory chamber in 10 healthy men. On 3 separate (7). In fact, long-term clinical trials have shown greater losses in occasions, subjects were randomly assigned among 3 treatments: body weight and body fat in obese patients treated with a combi- green tea extract (50 mg caffeine and 90 mg epigallocatechin gal- nation of caffeine and ephedrine than in those treated with late), caffeine (50 mg), and placebo, which they ingested at placebo, caffeine, or ephedrine alone (8).
Previous work in our laboratory, in which an in vitro system Results: Relative to placebo, treatment with the green tea extract
was used to measure the respiration rate of brown adipose tissue resulted in a significant increase in 24-h EE (4%; P < 0.01) and in rats, suggests that the interaction between caffeine and a significant decrease in 24-h RQ (from 0.88 to 0.85; P < 0.001) ephedrine resides in ephedrine’s induced enhancement of sympa- without any change in urinary nitrogen. Twenty-four–hour uri- thetic neural release of norepinephrine together with caffeine’s nary norepinephrine excretion was higher during treatment with ability to inhibit the phosphodiesterase-induced degradation of the green tea extract than with the placebo (40%, P < 0.05).
intracellular cyclic AMP (cAMP), and, to a lesser extent, caf- Treatment with caffeine in amounts equivalent to those found in feine’s antagonism of the negative modulatory effect of adenosine the green tea extract had no effect on EE and RQ nor on urinary on increased norepinephrine release (9). The net result, therefore, would be an elevated cellular concentration of cAMP—a critical Conclusions: Green tea has thermogenic properties and pro-
intracellular mediator for the actions of catecholamines on ther- motes fat oxidation beyond that explained by its caffeine content mogenesis. Apart from phosphodiesterases, adenosine, and certain per se. The green tea extract may play a role in the control of prostaglandins, the concentration of norepinephrine at the synap- body composition via sympathetic activation of thermogenesis, tic junction and its interaction with adrenoceptors is also likely to Am J Clin Nutr 1999;70:1040–5.
be negatively modulated through its enzymatic degradation,namely by catechol O-methyltransferase (COMT) (10). Given KEY WORDS
Obesity, thermogenesis, catechins, polyphenols, caffeine, sympathetic nervous system, green tea, fat oxidation,catecholamines, men 1 From the Department of Physiology, Faculty of Medicine, University of Geneva; Geneva University Hospital; and Laboratoires Arkopharma, INTRODUCTION
2 Supported in part by Arkopharma Laboratories and by the Swiss National Fundamentally, there are only 2 ways to treat obesity: reduce energy intake or increase energy expenditure (EE). Because ther- 3 Address reprint requests to AG Dulloo, Institute of Physiology, Univer- mogenesis and fat oxidation are to a large extent under the control sity of Fribourg, Rue de Musée 5, CH-1700 Fribourg, Switzerland. E-mail: of the sympathetic nervous system (SNS), approaches that mimic or interfere with the SNS and its neurotransmitter norepinephrine offer a rational approach for obesity management (1–3). In this Accepted for publication March 31, 1999.
Am J Clin Nutr 1999;70:1040–5. Printed in USA. 1999 American Society for Clinical Nutrition evidence that this enzyme can be inhibited by certain tea polyphe- important catechin polyphenol) in 2 capsules. The green tea nols (11), we recently investigated in our in vitro system whether extract (code name: AR25) was obtained by alcohol extraction an extract of green tea, by virtue of its high content of both caf- from dry tea leaves of unfermented Camellia sinensis, standard- feine and catechin polyphenols, could be an effective promoter of ized at 25% catechins, and commercially prepared in capsular thermogenesis. These in vitro results (12) can be summarized as form under the name Exolise (Arkopharma Laboratories, Nice, follows: 1) the green tea extract was found to be more effective France). Note that apart from (Ϫ)-epigallocatechin gallate, the than were equivalent amounts of caffeine in stimulating peripheral green tea extract also contains substantial amounts of other cat- tissue thermogenesis, and 2) this difference between the green tea echins: (Ϫ)-epigallocatechin, (Ϫ)-epicatechin, and (Ϫ)-epicate- extract and equimolar caffeine in activating thermogenesis was chin gallate. (Ϫ)-Epigallocatechin gallate constitutes ≥ 50% of much more marked under conditions of increased norepinephrine the total amount of tea catechins and is believed to be the most release because the synergistic interaction between the green tea pharmacologically active tea catechin (14). In the present study, extract and ephedrine on tissue thermogenesis was much more (Ϫ)-epigallocatechin gallate was found to constitute Ϸ72% of pronounced than that of caffeine or ephedrine.
total catechins, such that the amount of total catechins con- On the basis of these in vitro data, our main objectives in this sumed with each meal was 125 mg. Consequently, ingestion of study were 2-fold: 1) to examine the extent to which daily admin- capsules containing the green tea extract AR25 provided daily a istration of capsules containing a green tea extract (containing cat- total of 150 mg caffeine and 375 mg catechins, of which 270 mg echin polyphenols and caffeine in amounts comparable with those was epigallocatechin gallate. The various treatments in the res- commonly consumed in green tea beverages in Asian communi- piratory chamber were administered in a double-blind design ties) would stimulate thermogenesis and increase daily EE in and with a 5–10-d interval between successive 24-h trials for humans, and 2) to determine whether the effects of the green tea each subject. During the entire study period (lasting 5–6 wk), extract on the metabolic rate and substrate oxidation in humans the subjects were prescribed a weight-maintenance diet consist- would be greater than that explained by its caffeine content per se.
ing of Ϸ13% of energy as protein, Ϸ40% as fat, and Ϸ47% ascarbohydrates. During each respiratory chamber trial, this diet was considered the “basal diet,” which was fed at an energy SUBJECTS AND METHODS
level of 1.4 times the estimated basal energy requirements of thesubject, predicted from the regression equation of Cunningham Subjects
(15). Thus, during each of the subject’s 3 respiratory chamber Healthy young men were recruited from the student and staff trials, the following conditions were the same: energy intake, population of our University after complete medical and nutri- nutrient composition of the diet, sedentary lifestyle pattern tional histories were obtained by use of a questionnaire. Smok- (reading, listening to radio, watching television, etc), pattern of ers, competitive athletes, and persons who engaged in intense physical activity, meal pattern, and time period for sleeping. No physical activities or who had a history of weight loss were not methylxanthine-containing foods or beverages were consumed eligible for inclusion in the study. Inclusion criteria included 24 h before or during the stay in the respiratory chamber. Dur- body fatnesses ranging from lean to mildly obese (8-30% body ing the first 8 h of each trial, the heart rate was monitored with fat). All selected subjects habitually consumed a typical Western diet, with fat contributing 35–40% of dietary energy intake, andtheir estimated intake of methylxanthines (mostly as caffeine- Determination of daily energy expenditure and substrate
containing beverages) ranged from 100 to 200 mg/d. At the onset oxidation
of the study, body weight and height were measured and body fat EE was continuously monitored by indirect calorimetry dur- was determined by the method of Durnin and Womersley (13) ing the stay in the respiratory chamber, the details of which were from measurements of skinfold thicknesses taken at 4 sites with described previously (16). The respiratory chamber had a large a Harpenden skinfold caliper (British Indicators, Ltd, London); window overlooking the streets and was large enough (3 m long fat-free-mass (FFM) was calculated as the difference between ϫ 2.5 m wide ϫ 2.5 m high) to provide the comforts of a hotel.
body weight and body fat. Mean (± SEM) values for some of the It was furnished with a bed, resting armchair, table, wash basin physical characteristics of the 10 men participating in this study and water tap, dry toilet, audiovisual equipment (television, were as follows: age, 25 ± 1 y; height, 177 ± 3 cm; weight, video cassette recorder, radio, and tape recorder), intercom, and 78.7 ± 4.3 kg; body mass index (BMI; in kg/m2), 25.1 ± 1.2; per- a telephone. The door was fitted with a double window as well centage body fat, 18.2 ± 1.8%; and FFM, 63.8 ± 2.5 kg. The as an air-lock system through which food and other items were study was approved by the Ethical Committee for Human Exper- provided. Complete privacy was obtainable by pulling a curtain imentation of the University of Geneva and was conducted in over the windows. The chamber was sufficiently airtight to accordance with its rules and regulations.
ensure that air left only through the apparatus that measures itsflow rate and gas concentrations. A pump removed air continu- Experimental design
ously from the chamber at a rate that could be varied from Each subject spent 24 h in our respiratory chamber on 3 sep- between 50 and 100 L/min, which passed through a mass flow arate occasions and was randomly assigned to receive 1 of the meter for continuous measurement of the flow rate. The effect of following 3 treatments orally (in capsular form) 3 time/d (ie, pumping air out resulted in air entering the chamber through a 2 capsules with breakfast, lunch, and dinner): 1) a green tea special inlet placed in the wall opposite the location where the extract containing 50 mg caffeine and 90 mg epigallocatechin air left. A fan ensured that the air was mixed inside the chamber gallate, 2) 50 mg caffeine, or 3) a placebo that consisted of cel- and a thermostat ensured the maintenance of a constant and lulose as inert filler. The dosages represented the amount of caf- comfortable temperature. Air samples entering and leaving the feine and epigallocatechin gallate (the quantitatively most chamber passed through differential analyzers for continuous measurements of differences in oxygen and carbon dioxide con- tents between extracted air and inlet air. These data were contin- Energy expenditure (EE) during diurnal, nocturnal, and total 24-h uously fed into an online computerized data acquisition system, from which EE and the respiratory quotient (RQ) were calcu- lated throughout the measurement periods. Measurements were accurate within 1–2%, as described previously (16). The oxida-tion rates of protein, carbohydrate, and fat were calculated from 24-h EE, RQ, and urinary nitrogen excretion for each 24-h stay 1 x– ± SEM; n = 10.
Measurement of urinary nitrogen and catecholamines
2 For differences across treatments (ANOVA).
3 Significantly different from placebo, P < 0.05 (post hoc pairwise com- During each subject’s stay in the respirometer, urine was col- lected into 2 or more 2-L opaque glass containers (containing 10 mL 4 Significantly different from caffeine, P < 0.05 (post hoc pairwise com- of 5 mol HCl/L each) over 2 periods to reflect diurnal and noc- turnal phases, with the time intervals indicated below. After the24-h collection period was complete, all urine samples werestored at Ϫ20 ЊC until assayed for nitrogen with an autoanalyzerby the method of Kjeldahl and for epinephrine, norepinephrine, 24-h periods. Treatment with the green tea extract yielded signi- and dopamine concentrations by liquid chromatography with ficantly lower values than did the other 2 treatments during all 3 periods. Individual changes indicated that the RQ in most ofthe subjects (8 of 10) was substantially lower (differences > 0.01) Data presentation
after the green tea extract than after the placebo; in 4 of these sub- EE, RQ, substrate oxidation, and urinary catecholamine data jects the difference was ≥ 0.04. However, no correlation was are reported as diurnal (corresponding to the first 15 h in the res- observed between the magnitude of reduction in the RQ and the piratory chamber, from 0800 to 2300), nocturnal (from 2300 to degree of fatness (BMI or percentage of body fat) of the subjects.
0800 the next morning), and total 24-h values.
Because urinary nitrogen losses (and hence protein oxidation) indicated no significant differences across treatments for all Statistics
3 periods, the lower RQ during treatment with the green tea Repeated-measures analysis of variance was used to deter- extract was due to a shift in substrate utilization in favor of fat mine significance. When statistically significant differences oxidation. As indicated in Table 3, carbohydrate oxidation was
were detected, a post hoc pairwise comparison across treat- significantly lower (P < 0.01) and fat oxidation was significantly ments was performed by using Tukey’s test. Significance was higher (P < 0.001) after the green tea extract than after the set at a P value < 0.05. The statistical analyses were performed placebo. By contrast, there were no significant differences in by using the computer software program STATISTIK 4.0 (Ana- substrate oxidation between the caffeine and placebo groups.
The relative contribution of protein, carbohydrate, and fat oxida-tion to daily EE are also presented in Table 3. The contributionof fat oxidation to 24-h EE during treatment with the green tea extract (41.5%) was significantly higher (P < 0.001) than duringplacebo treatment (31.6%).
Energy expenditure
Urinary excretion of catecholamines
Mean (± SEM) diurnal, nocturnal, and total 24-h EE values are presented in Table 1. Significant differences across treatments
Urinary excretion values of catecholamines during the study were observed only for diurnal and total 24-h EE. Diurnal EE are shown in Table 4. Urinary epinephrine and dopamine were
was higher during treatment with the green tea extract than dur- not significantly different across treatments in any of the 3 peri- ing treatment with placebo or caffeine, by 4.5% and 3.2%, ods. Urinary norepinephrine and its precursor dopamine tended respectively, but significantly so only for the green tea extract.
to be highest during treatment with the green tea extract, although Total 24-h EE with the green tea extract, however, was signifi- differences across treatments were only significant for total 24-h cantly higher than that with both the placebo and caffeine, by 3.5% and 2.8%, respectively. There were no significant differ- Heart rate
ences in diurnal, nocturnal, or total 24-h EE between the caffeineand placebo groups. Individual changes (relative to placebo) in None of the subjects reported any side effects and no signi- total 24-h EE indicated an increase in only 2 subjects after caf- ficant differences in heart rates across treatments were observed feine treatment, but an increase in 6 of the 10 subjects after treat- during the first 8 h that the subjects were assessed in the respi- ment with the green tea extract, ranging from 266 to 836 kJ (mean or median of Ϸ330 kJ). No correlation was observedbetween the magnitude of thermogenic response and the degreeof fatness (BMI or percentage of body fat) of the subjects.
Although both coffee and tea are widely consumed world- Respiratory quotient and substrate oxidation
wide, our knowledge of their influence on energy metabolism RQs are shown in Table 2. Significant differences across
has been limited to studies of coffee or to its main pharmacolog- treatments were found during the diurnal, nocturnal, and total ically active ingredient caffeine. Therefore, the results of the TABLE 2
Respiratory quotient (RQ) during diurnal, nocturnal and total 24-h periods1
1 x– ± SEM; n = 10.
2 For differences across treatments (ANOVA).
3 Significantly different from placebo and caffeine, P < 0.05 (post hoc pairwise comparison with Tukey’s test).
present investigation are the first to show in humans that tea been reported with dosages of 600–1000 mg caffeine/d (18, 19).
(albeit green tea) also has the potential to influence EE and sub- It is therefore not surprising that in the present study, the admin- strate utilization. Because dietary energy intake and diet compo- istration of caffeine alone (< 100 mg with each meal) failed to sition were identical during all treatments and because the subjects increase daily EE. Nonetheless, the amount of caffeine con- maintained the same feeding and physical activity patterns dur- sumed during treatment with the green tea extract may have ing each 24-h respiratory chamber trial, the 4% increase in reached the critical dose, which, although ineffective by itself, 24-h EE during treatment with the green tea extract essentially may have enabled a synergistic interaction with other bioactive reflects its stimulatory effect on thermogenesis. Furthermore, ingredients in the green tea extract to promote catecholamine- despite the absence of differences in urinary nitrogen excretion, induced thermogenesis and fat oxidation.
and hence in protein oxidation rates, the observed reductions inRQ during treatment with the green tea extract suggest that fat Mechanism of action
oxidation was higher and carbohydrate oxidation was lower dur- Green tea is well known for being particularly rich in ing this period than during the placebo period. Indeed, calcula- flavonoids (14), and several of these polyphenols—particularly tions of the relative contribution of substrate oxidation to daily the subclass of flavonoids commonly known as tea catechins— EE indicated that the contribution of fat oxidation to 24-h EE, have been shown in vitro to inhibit COMT (11), the enzyme that which was 31.6% with the placebo, was higher (41.5%) with the degrades norepinephrine. Given the important role of the SNS green tea extract. Of particular interest in this study was that the and its neurotransmitter norepinephrine in the control of thermo- effects of the green tea extract in enhancing thermogenesis and genesis and fat oxidation, it is conceivable that these catechins, fat oxidation could not be explained solely on the basis of its caf- by inhibiting COMT, result in an increase in or a more prolonged feine content because treatment with an amount of caffeine effect of norepinephrine on thermogenesis and fat metabolism or equivalent to that in the extract failed to alter EE, RQ, or sub- both. Support for this contention comes from our previously strate oxidation. The implication of this finding is that these reported in vitro studies on the respiration rate of brown adipose metabolic effects resulted from ingredients other than caffeine in tissue, which indicated that 1) a green tea extract (rich in cate- the green tea extract. The most likely explanation for the lack chin polyphenols and to a lesser extent in caffeine) was more of a thermogenic effect of caffeine is that the dosage (50 mg potent than were equimolar concentrations of caffeine alone in 3 times/d) was below the threshold for stimulating thermogene- stimulating the respiration rate of brown adipose tissue (12), sis. On the basis of data from the literature, a single oral dose of 2) the thermogenic effect of a green tea extract was markedly ≥100 mg caffeine is required to produce a thermogenic response potentiated by enhancing the release of norepinephrine from the sustainable for ≥ 1–2 h, and a stimulatory effect of caffeine per sympathetic nerve terminals with the use of ephedrine (12), and se on 24-h EE under respiratory chamber conditions has only 3) the thermogenic effect of a green tea extract could be mimic-ked by epigallocatechin gallate (20). Furthermore, the assay ofurinary catecholamines in the present study of humans showeda tendency for urinary norepinephrine (and its precursor dopamine), but not for epinephrine, to be higher in most subjects Substrate oxidation during 24 h in the respiratory chamber1 during treatment with the green tea extract; however, differences across treatments were only significant for total 24-h norepi- nephrine excretion. This observation is consistent with the inhibiting effect of green tea on COMT, the consequential reduc- tion in norepinephrine degradation, and hence, the spillover of norepinephrine into the circulation, thereby accounting for the higher urinary excretion of norepinephrine. Such effects, result- ing in a prolonged life of norepinephrine in the sympathetic synaptic cleft, could explain the observed effects of the extract in stimulating thermogenesis and fat oxidation.
It can be argued, however, that other tea flavonoids—such as 1 x– ± SEM; n = 10.
quercetin and myricetin, which have also been shown to inhibit 2 For differences across treatments (ANOVA).
3 COMT in vitro (11)—may also have played a role in the meta- Significantly different from placebo, P < 0.05 (post hoc pairwise com- bolic effects of the green extract observed in the present study.
However, there are only minute amounts of these flavonoids in Significantly different from placebo and caffeine, P < 0.05 (post hoc pairwise comparison with Tukey’s test).
green tea and their absorption when taken orally is doubtful, par- ment of daily EE. This thermogenic effect of the extract (an Urinary catecholamines during diurnal, nocturnal, and total 24-h periods1 increase of 328 kJ/d) was comparable with increases in daily EEseen in previous studies with much higher doses of caffeine in postobese and lean subjects (increases of 400 kJ) (18); however, only half of the thermogenic stimulation was the result of a com- bination of ephedrine and caffeine (800 kJ) (23). The results of these studies together with the results of our in vitro studies in brown adipose tissue—which indicate that the stimulatory effect of the extract on tissue thermogenesis was markedly potentiated in the presence of ephedrine (12, 20)—raise the possibility that the effect of the green tea extract could be greater under condi- tions of elevated sympathetic tone and norepinephrine release (ie, higher activity of COMT), such as during concomitant treatment with drugs that enhance norepinephrine release or when activity levels are higher than those under the confined and sedentary conditions of a respiratory chamber. Second, the differences in 1 x– ± SEM; n = 10.
substrate utilization in favor of fat oxidation (lower RQ) in 2 For differences across treatments (ANOVA).
response to the green tea extract were much more consistent than 3 Significantly different from placebo, P < 0.05 (post hoc pairwise com- were the differences in EE because lower RQs with the extract than with the placebo were observed in most of the subjects, including in those subjects who did not show a higher EE. Thisfinding with the green tea extract is even more remarkable whencompared with data indicating that caffeine ingestion alone, even ticularly because of evidence that flavonoids in food cannot gen- at doses as high as 1000 mg/d, had no significant effect on the erally be absorbed from the small intestine because they are RQ during the diurnal or nocturnal period (19). Third, stimula- bound to sugars as glycosides. By contrast, catechins are not tion of thermogenesis and fat oxidation by the green tea extract only present in large quantities in green tea, but they are known was not accompanied by an increase in heart rate. In this respect, to be better absorbed than are flavonoids. Indeed, substantial the green tea extract is distinct from sympathomimetic drugs, amounts of epigallocatechin gallate, epigallocatechin, and epi- whose use as antiobesity thermogenic agents is limited by their catechin have been measured in the plasma of human volunteers adverse cardiovascular effects and, hence, are particularly inap- after ingestion of green tea powder, with peak plasma concentra- propriate for obese individuals with hypertension and other car- tions of catechins (nonconjugated) after 3 h of 3–3% of the ingested dose (21, 22). It is not known whether the relatively low Conclusion
ratios of circulating catechins to ingested catechins can be attrib-uted to an efficient metabolism or to uptake by other tissues.
In conclusion, oral administration of the green tea extract However, the tissue concentrations of at least one of these tea stimulated thermogenesis and fat oxidation and thus has the catechins must have been high enough in our study to exert bio- potential to influence body weight and body composition via logical effects, as indicated by the stimulatory effect of the green changes in both EE and substrate utilization.
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CHAPTER 2 LITERATURE REVIEWS 2.1 Risperidone (Risperdal®) is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives. The chemical designation is 3-[2-[4-(6-fluoro-1, 2-benzisoxazol- 3-yl)-1-piperidinyl] ethyl]-6,7,8,9-tetrahydro- 2-methyl-4H-pyrido [1,2-a]pyrimidin- 4-one. Its molecular formula is C23H27FN4O2 (Figure 1) and its molecular weight is 410.49

CHIROPRACTIC THERAPY CENTER Phone: (713) 670-7760 Fax: (713) 670-7761 NUTRITION EVALUATION: 10/27/2011 PATIENT INFORMATION DATA USED FOR ANALYSIS Height: 5'6"Weight: 145Blood Pressure: 139 / 95O2 Level: 83%Heart Rate: 98 PRIMARY SYMPTOMS 1. Hypercholesterolemia (High Cholesterol)2. High blood pressure3. Tachycardia (High Heart Rate)4. Diabetes Mellitus PRESENTING SYMPTOMS All

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