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Institute of Physiology University of Fribourg Rue du Musée 5 CH-1700 Fribourg Switzerland E-mail: abdul.dulloo{at}unifr.ch
Dear Sir:
I am grateful to Kao et al for their interesting compilation of recent data about the effects of epigallocatechin gallate (EGCG)—the most abundant catechin of green tea—on various variables in vitro and in vivo, which collectively underscore the potential antiobesity properties of this polyphenol. Nobody will disagree with their final remark that the use of purified components are necessary for identifying the active components that confer green tea (or any other phytoproduct) with potential antiobesity properties. In fact, as a follow-up to our in vivo study that indicated the ability of a green tea extract particularly rich in EGCG to stimulate thermogenesis in lean and overweight humans (1), we also investigated the effect of pure (-)-EGCG on tissue respiration rate in vitro. We showed its dependency on sympathetically released norepinephrine (NE) in the activation of peripheral thermogenesis (2). There is clearly a need for further studies investigating the effects of EGCG on long-term energy balance and substrate utilization in animal models and in humans. Toward this end, it is important to clarify and to explore some of the issues raised by Kao et al.
First and foremost, we feel that an important aspect of our studies pertaining to green tea and thermogenesis was missed by Kao et al: it is not EGCG alone, but the combination of EGCG and caffeine—via their interactions with sympathetically released NE—that confers green tea with its ability to enhance thermogenesis. Although this proposal is largely speculative, on the basis of our human studies measuring energy expenditure and urinary catecholamines (1), it is strongly supported by our in vitro studies in brown adipose tissue fragments, which indicate that EGCG is a rather weak stimulus of thermogenesis and that the thermogenic potency of green tea resides in a synergistic interaction between the 2 main pharmacologically active ingredients of green tea—EGCG and caffeine—and sympathetically released NE (2). The mechanisms behind these synergistic interactions are to be expected because EGCG and caffeine act in concert along different control points underlying NE-induced thermogenesis, namely that EGCG inhibits the enzyme catechol-O-methyltransferase that degrades NE within the synaptic cleft (3), whereas caffeine inhibits primarily the phosphodiesterase enzyme complex that degrades cyclic AMP, the intracellular secondary messenger for NE-mediated thermogenesis. The net result of the combination of EGCG and caffeine may, therefore, be a reduction in the effects of 2 brakes along the pathway of NE-activated thermogenesis. One would therefore expect the combination of EGCG and caffeine to be more effective than caffeine alone in potentiating thermogenesis under sympathetic neural control, such as in response to meals or to physical activity.
Second, the new data presented by Kao et al pertaining to the anorectic properties of injected EGCG in rats raise questions about the availability of this catechin to various tissues. At such high doses of EGCG—likely to be achievable only by injection, given the poor absorption of this catechin when taken orally—one wonders about the relevance of these suprapharmacologic doses vis-à-vis the effect of oral consumption of green tea on food intake. In our human studies, although conducted over only 1 d in a calorimeter, none of the subjects had a reduced food intake after green tea treatment or indicated that consumption of the green tea extract altered their "feeling of fullness." These findings are in sharp contrast with the results of our previous study—also conducted over just 1 d in a calorimeter—that investigated the thermogenic properties of a combination of ephedrine, caffeine, and theophylline. In that study, postobese subjects had not only an 8% increase in 24-h energy expenditure but also a 16% decrease in 24-h energy intake (4). Although this "cocktail," particularly one of its ingredients—ephedrine—is well known for its effects on the central nervous system, 2 intriguing questions arose from the animal studies reported above by Kao et al: are the observed anorectic effects after EGCG injection also centrally mediated and, if so, can EGCG or its metabolites cross the blood-brain barrier? Alternatively, could it be that when EGCG is administered long term, its appetite-suppressing effect is not direct, but via its effects in enhancing fat oxidation, which in our acute human study was much more impressive than was the increase in energy expenditure. According to the nutrient balance theory, the balance between fat oxidation and fat intake (unlike for carbohydrate and protein balances) is not precisely regulated and the failure to increase fat oxidation in response to excess fat intake will result in increased appetite and obesity. Consequently, EGCG, by promoting fat oxidation irrespective of whether it stimulates energy expenditure, could be of value in minimizing the tendency for hyperphagia associated with our typical high-fat, energy-dense diets.
Last, the current surge of interest in green tea and its potential role in the management of obesity must be put into the wider context of the interest by the public, media, and industry in functional foods, nutraceuticals, and many different so-called natural supplements (the supply and demand theory operating at its very best!). Green tea, which has high catechin and caffeine contents, is only the latest addition to an increasing list of dietary ingredients now known to be capable of stimulating thermogenesis and fat oxidation by interfering with the sympathoadrenal system. These include the capsaicinoid compounds, which confer pungency to spicy ingredients such as chilies, mustard, and red pepper; the methylxanthines (eg, caffeine) found in beverages such as coffee and tea; the medium-chain-triacylglycerols found in coconut oil, which is the main cooking oil in many parts of Asia and Africa; and the combination of catechins and caffeine found in green tea and consumed widely in China and Japan. They have all been shown to stimulate thermogenesis, fat oxidation, or both in humans in amounts compatible with their daily intake in the diet of specific communities (1, 6–10). One wonders, therefore, about the extent to which these ingredients, which are consumed in the diets of most cultures today, could already be helping many of us to burn excess dietary fat, but also as to what type of safety and efficacy standards to which they should be subjected before being advocated as supplements for the purpose of managing obesity.
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