The global prevalence of obesity has increased considerably in the last decade. Tools for obesity management, including consumption of caffeine, capsaicin and different teas such as green, white and oolong tea, have been proposed as strategies for weight loss and weight maintenance, as they may increase energy expenditure (4–5%), fat oxidation (10–16%) and have been proposed to counteract the decrease in metabolic rate that is present during weight loss. Daily increases in thermogenesis of approximately 300–400 kJ can eventually lead to substantial weight loss. However, it becomes clearer that certain conditions have to be met before thermogenic ingredients yield an effect, as intra-variability with respect to body weight regulation has been shown between subjects. Furthermore, the sympathetic nervous system is involved in the regulation of lipolysis, and the sympathetic innervation of white adipose tissue may have an important role in the regulation of total body fat in general. Taken together, these functional ingredients have the potential to produce significant effects on metabolic targets such as satiety, thermogenesis and fat oxidation. A significant clinical outcome may sometimes appear straightforward and may also depend very strongly on full compliance of subjects. Nevertheless, thermogenic ingredients may be considered as functional agents that could help in preventing a positive energy balance and obesity.
Overweight and obesity represent a rapidly growing threat to the health of populations in an increasing number of countries.1 The ultimate cause of obesity is an imbalance between energy intake and energy expenditure (EE).2 A negative energy balance is needed to produce weight loss and can be achieved by either decreasing intake or increasing expenditure.3, 4 Among others, stimulation of EE (or the prevention of its decline during dieting) by the use of natural herbal ingredients such as teas, caffeine and capsaicin has attracted interest, especially because these ingredients do not contain any energy themselves, yet stimulate expenditure of energy. Green tea (GT), oolong tea (OT) and white tea (WT) are consumed primarily in China, Japan and a few countries in North Africa and the Middle East.5, 6 Tea is made from the leaves of Camellia sinensis L. species of the Theaceae family, GT being the non-oxidized, non-fermented product, OT the semioxidized, semifermented product; WT is made from the youngest buds of the plant that undergo even less processing than GT. As a consequence of this, all teas contain high quantities of several polyphenolic components such as epicatechin, epicatechin gallate, epigallocatechin and, the most abundant and probably the most pharmacologically active, epigallocatechin gallate.7 Tea leaves that have been processed the least contain the most catechins.
From caffeine, that is also present in GT, it has been reported that it has thermogenic effects and can stimulate fat oxidation in vitro, in part through sympathetic activation of the central nervous system.8 In humans, caffeine has been shown to stimulate thermogenesis and fat oxidation.9, 10, 11 GT extracts, containing caffeine and catechin-polyphenols, have been reported to have an effect on body weight7, 12 and EE.12, 13, 14 The observation that GT stimulates thermogenesis cannot be completely attributed to its caffeine content because the thermogenic effect of GT extract containing caffeine and catechin-polyphenols is greater than that of an equivalent amount of caffeine.13
Finally, capsaicin is the major pungent principle in red hot pepper. Hot peppers or capsium species are used in food products and as spices worldwide, but especially in Asia it is very commonly used.15 Over the last decade, capsaicin has been studied for its thermogenic and satiating capacities.
Although there may be more thermogenic ingredients than the ones listed here, these are the most promising and have been primarily studied with respect to body weight regulation.
Efficacy of GT, OT and WT
Green tea has been well studied in the short term13, 16, 17, 18, 19, 20 (Table 1) and over the long term21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 (Table 2). EE and fat oxidation in the short term and weight loss and weight maintenance (WM) in the long term are the key issues that most of the studies have focused on. A recently published meta-analysis about the effects of GT on weight loss and WM, which included most of the long-term studies presented in Table 2, showed that GT significantly attributed to weight loss and prevents weight regain with on average 1.3 kg.36 On the basis of the collected data from all the conducted studies so far, GT seems to be a promising agent for body weight regulation. Its fellow members of the tea family, OT and WT, have not been studied very extensively. OT's long-term effects22, 37, 38, 39, 40 are more investigated than its acute effects.18, 41 No studies have been conducted so far that address the effects of WT on thermogenesis and body weight. Biochemical analyses, however, do show differences between the different processed teas. WT has been shown to contain the largest amount of catechins, from which EGCG is also present abundantly. The amount of caffeine in WT is also substantially larger compared with for instance GT.42, 43, 44, 45 More research is needed to study WT's effect on thermogenesis.
Green tea and high-protein diet
As GT (epigallocatechin gallate+caffeine) and protein have both shown to improve body WM after weight loss, it was investigated whether the effect of a GT–caffeine mixture, added to a high-protein diet (HP), on WM after body weight loss in moderately obese subjects would have a synergistic effect.46 In a randomized placebo-controlled double blind parallel trial in 80 overweight and moderately obese subjects (age: 44±2 (s.d.) years; body mass index: 29.6±2.0 kg m−2), matched for gender, age, body mass index, height, body mass and with a habitually low-caffeine intake, a very low-energy diet intervention during 4 weeks was followed by 3 months WM. During the WM period, the subjects received a GT–caffeine mixture (270 mg epigallocatechin gallate+150 mg caffeine per day), or placebo, both in addition to an adequate protein diet (AP: 50–60 g protein per day) vs a HP (100–120 g protein per day). Subjects lost 7.0 kg±1.6, or 8.2%±2.0 body weight (P<0.001). During the WM phase, WM, resting energy expenditure, fat-free mass were relatively increased, in both the HP groups and in the AP+GT–caffeine mixture group (P<0.05), whereas respiratory quotient and body fat (free mass) were reduced, all compared with the AP+placebo group. Satiety was only increased in both HP groups (P<0.05). The GT–caffeine mixture was only effective in the AP diet. The authors conclude that a GT–caffeine mixture and an HP improved WM independently, through thermogenesis, fat oxidation, sparing fat-free mass, and for the HP through satiety; yet a possible synergistic effect failed to appear.46
Mechanisms of action
Teas and caffeine
Catechins in tea inhibit the enzyme catechol O-methyltransferase (COMT) that is present in almost every tissue and degrades catecholic compounds such as norepinephrine (NE)13, 24 (Figure 1). COMT decreases the hydrophilicity by methylation, followed by sulfation and glucuronidation to make the excretion in urine and bile possible.47 NE cannot be degraded through the inhibition of COMT, and consequently the sympathetic nerve system (SNS) will be stimulated continuously due to the presence of NE, which attaches to β-adrenoceptors and causes an increase in EE and fat oxidation.48 The SNS has an important role in the regulation of energy homeostasis but the above-described phenomenon does not always appear equally clear in all ethnic groups. For instance, studies with Asian subjects seem to report more positive results than studies with Caucasian subjects. This may be caused by differences in relevant enzyme activity, causing differences in sensitivity for these ingredients. In that respect, Hodgson et al.49 stated that there is a wide variability in flavonoid O-methylation, a major pathway of flavonoid metabolism, by the enzyme COMT. The inter-individual variability of the activity of COMT could vary as much as threefold. Moreover, there is evidence that there is a difference in COMT enzyme activity between ethnic groups.50 Asian populations have a higher frequency of the thermostable, high activity enzyme, COMTH allele (Val/Val polymorphism) than the Caucasian populations. The Caucasian populations have a higher frequency of the thermolabile, low activity enzyme, COMTL allele (Met/Met polymorphism).50 Fifty percent of the Caucasians are homozygous for the COMTL allele (25%) and COMTH allele (25%). The other 50% is heterozygous (Val/Met polymorphism).50 This may explain the difference in sensitivity to interventions with GT–caffeine mixtures, and why, in some studies with Caucasian subjects, no effect was seen after ingestion of GT.
As caffeine is also present in tea, its effect will also take place after tea consumption. Caffeine affects the thermogenesis by inhibiting the enzyme phosphodiesterase. This enzyme degrades intracellular cyclic amino mono phosphate.51 Phosphodiesterase usually hydrolyses cyclic adenosine monophosphate (cAMP) to AMP, but after consumption of caffeine, cAMP concentration rises and SNS activity will be increased and inactive hormone-sensitive lipase will be activated, which promotes lipolysis.52 The SNS activity and lipoysis are dependent on cAMP, because cAMP activates the protein kinase A.53 Besides the inhibition of phosphodiesterase, caffeine also affects the thermogenesis through the stimulation of substrate cycles such as the Cori-cycle and the FFA-triglyceride cycle.10 Caffeine is a methylxanthine, which has a thermogenic impact. In the Cori cycle, lactate moves from the muscles to the liver, where it will be converted into pyruvate. The pyruvate will be converted to glucose by the enzyme lactate dehydrogenase and circulate back to the muscles through the blood.10 Acheson et al.52 showed that FFA turnover and lipid oxidation are increased after the consumption of caffeine but that it requires a large increase in FFA turnover to have a small increase in lipid oxidation. Nonoxidative lipid turnover, the hydrolysis and reesterification of triacylglycerol, is greater than the increase in oxidative lipid disposal.52 They also found that caffeine antagonizes the inhibitory effects of adenosine on lipolysis by adenylyl cyclase. Nonadrenergic thermogenic mechanisms can also be involved, as caffeine antagonizes the ryanodine receptor, the calcium ion release channel of sarcoplasmatic reticulum in skeletal muscle that for instance increases glycolysis and adenosine triphosphate turnover after stimulation.52
Catechins and caffeine inhibit two enzymes, which interrupt the pathway of NE-activated thermogenesis.54 As SNS activity is determined by the concentration of NE, more NE means a higher activity and increased EE. SNS activity regulates the resting metabolic rate, which is the largest component of the daily EE. NE makes it possible to increase the usage of adenosine triphosphate through ion pumping and substrate cycling.14 The rate of mitochondrial oxidation is also involved in the increased thermogenesis due to the poor coupling of adenosine triphosphate synthesis, which leads to heat production. Catechins also have a direct effect on the gene expression of different uncoupling proteins (UCPs) that influence the thermogenesis with the production of heat.55 Gene expression of the UCPs also increases when cAMP activates the protein kinase A, after the inhibition of phophodiesterase by caffeine.56 The protein kinase A stimulates hormone-sensitive lipase, which increases the concentration of free fatty acids by the conversion of triglycerides. UCP activity will be enhanced through this.56
The increase in EE is accompanied by a change in substrate oxidation, as Dulloo et al. showed an increase in fat oxidation after the supplementation of GT.13 Another mechanism is triggered by the tea catechins that block the nuclear factor-κB activation by inhibiting the phosphorylation of inhibitor of κB.57 Nuclear factor-κB is an oxidative stress-sensitive transcription factor that regulates the expression of several genes, which are important in cellular responses such as inflammation and growth.57 Nuclear factor-κB is no longer able to inhibit the peroxisome proliferator-activated receptors that are important transcription factors for lipid metabolism.58 The mRNA expression of lipid-metabolizing enzymes, such as acyl-CoA oxidase and medium chain acyl-CoA dehydrogenase, is upregulated. Acyl-CoA oxidase is a peroxisomal β-oxidation enzyme and medium chain acyl-CoA dehydrogenase is a mitochondrial β-oxidation enzyme in the liver.58 The upregulation of these lipid-metabolizing enzymes makes it clear that β-oxidation activation after the supplementation of tea catechins is enhanced followed by an increase in fat oxidation.
With respect to the failure to show synergy between effects of a GT–caffeine mixture and an HP, the following mechanisms may shed light on this issue.46 Already in 1963, it was reported that proteins formed complexes with the polyphenols in tea. Especially caseins, which are present in milk protein, tend to bind the polyphenols.59 In the absence of caseins, α-lactalbumin and β-lactoglobulin can form complexes with the flavonoids. The protein ‘wraps’ itself around the catechins, a process named non-covalent crosslinking. This process might reduce the bioavailability and accessibility of the polyphenols.60 There is still some controversy about whether addition of milk to tea inhibits the beneficial effects of tea drinking. In an epidemiological study in a Welsh population, tea drinking appeared to be associated with a higher risk of developing coronary heart diseases.61 This was in contrast to the results of a comparable study in a Dutch population, where tea drinking was inversely associated with coronary heart diseases. The only difference between the populations, as both consume mainly black tea, is that people in Great Britain add milk to their tea. Addition of milk to tea lowered the concentrations of catechins in vitro, together with a significant reduction of the endothelial function after tea with milk in comparison with tea alone. The added milk lowered the vascular protective effects of tea, and the antioxidant capacity of tea to a maximum of 28%.62 The fat content of milk is not of importance, yet the interactions between flavonoids and proteins impede the gastric hydrolysis and thereby reduce the absorption of the polyphenols. It was also found that total antioxidant capacity was not lowered due to the addition of milk to tea, but the polyphenols were rather unavailable for absorption as the polyphenol–protein complexes were resistant to gastric hydrolysis. Moreover, absorption may be reduced because the pH of the stomach changes through the milk. The polyphenols have weak acid compounds that are easily absorbed in their non-ionised form. If the pH in the stomach rises due to the addition of milk, this can increase the ionization, which impedes the passage of the polyphenols through the gastric mucosa.63 In contrast, studies have shown no lowered antioxidant potential but a delay through the interference with absorption by milk. From the different explanations, the most proclaimed is the reduction in absorption after the formation of a protein–polyphenol complex that is resistant to gastric hydrolysis. The formation of such complexes takes place in the upper part of the digestive tract. If the complexes would be resistant to gastric hydrolysis from the beginning of the gastrointestinal system and therefore cannot be absorbed, how is it then possible that the HP+GT–caffeine mixture group has nearly the same effect as the HP+placebo group and the AP+GT–caffeine mixture group from which the proteins and polyphenols are absorbed? Most presumably, there is a surplus of proteins such as α-lactalbumin and β-lactoglobulin that only binds to flavonoids during the absence of caseins. These proteins may still be absorbed when the rest has formed complexes with polyphenols and they are known for their ability to reduce energy intake by a hunger suppressive effect, increase diet-induced thermogenesis and preserve lean body mass at the expense of fat mass.46
Safety of tea administration
Tea has been widely consumed in China and Japan for many centuries and is considered safe. A possible side effect of GT consumption is a minor increase in blood pressure as seen by Berube-Parent et al.17 They observed a nonsignificant increase (7 mmHg) in 24 h systolic blood pressure accompanied by a significant increase (5 mmHg) in 24 h diastolic blood pressure. No increase in heart rate was seen.17 This small short-term increase in blood pressure induced by GT might be neglected, as systolic blood pressure, diastolic blood pressure and heart rate were not affected by GT in other short-term13 or long-term research.12, 26
Efficacy of caffeine
For many years caffeine is known for its stimulating properties and the thermogenic effects have been extensively examined. Besides enhancing EE, caffeine also affects energy intake. However, these acute effects9, 10, 11, 13, 19, 41, 52, 64, 65, 66, 67 have not resulted into a successful long-term approach yet68 (Table 3). Only in a prospective study from Lopez-Garcia et al.,69 who studied the effect of caffeine on long-term weight change in a cohort, it was found that people who increased the caffeine consumption over 12 years gained less weight than those who decreased the caffeine consumption. Previous studies suggest that sensitivity to caffeine may be lost over time, which means that body weight regulation cannot be sustained for a longer period of time while receiving the same dosage.
Safety of caffeine administration
Caffeine appears to be a safe thermogenic agent for weight control. In adults, the short-term lethal dose for caffeine is estimated at 5–10 g day−1 (either intravenously or orally), which is equivalent to 75 cups of coffee, 125 cups of tea or 200 cola beverages.70 Long-term ingestion of caffeine has been suggested to have some minor adverse effects on human health. Astrup et al.10 observed only small and insignificant changes in blood pressure and pulse rate after 100 and 200 mg caffeine. In contrast, 400 mg caffeine significantly increased systolic and diastolic blood pressure by an average value of 6.3 mmHg. Furthermore, after 400 mg caffeine, significantly more subjects reported side effects such as palpitation, anxiety, headache, restlessness, dizziness compared with placebo.10 Robertson et al.71 administrated 250 mg oral caffeine to nine subjects who were not used to coffee. Systolic blood pressure increased 10 mmHg 1 h after caffeine consumption. Heart rate showed a decrease after the first hour followed by an increase above baseline after 2 h.71 However, in a subsequent study that examined the chronic effects of caffeine ingestion (150 mg day−1 for 7 days), tolerance to these effects was developed after 1–4 days.72 Thus no long-term effects of caffeine on blood pressure, heart rate or plasma rennin activity were demonstrated. Furthermore, in the short term, Bracco et al.11 did not find a significantly altered heart rate during the day after 4 mg caffeine per kg body weight was consumed five times daily. Accordingly, the use of caffeine is relatively safe, as it is quite certain that, although acute caffeine consumption may alter some cardiovascular variables, chronic ingestion of caffeine has little or no health consequences.
Efficacy of capsaicin
Studies concerning the thermogenic effects of capsaicin are mainly conducted in Asian populations, where it is more common in the daily food pattern. Effects on energy intake and EE in the short term are evident in such populations.15, 73, 74, 75, 76, 77, 78, 79 Nevertheless, hardly any long-term studies have been conducted with Asians. In the long-term studies with Caucasians,80, 81 compliance often seems to be the problem and therefore fail to result in negative body weight regulation. Although it was suggested that the effect of capsaicin is based on accumulation,78 dosages are often too low in Caucasian studies . The use of CH-19 Sweet pepper, which is the fruit of a non-pungent cultivar of pepper, might be the solution for the compliance issue.
Mechanisms of action
Capsaicin has been reported to increase thermogenesis by enhancing catecholamine secretion from the adrenal medulla in rats, mainly through activation of the central nervous system (Figure 2). Increase in thermogenesis induced by capsaicin is probably based on β-adrenergic stimulation. Both animal and human studies showed that the increase in thermogenesis is abolished after administration of β-adrenergic blockers such as propranolol. The upregulation of UCPs 1 and 2 after capsiate administration in animals was showed by Masuda et al.82 and believed to be responsible for the increase in thermogenesis. However, in a more recent study it was shown that UCP 3 was downregulated after capsiate treatment. This reduced UCP-3 gene expression was accompanied with an increase in the mitochondrial adenosine triphosphate production.83 Furthermore, the presence of a functional capsaicin-like vanilloid receptor in the vasculature of the rat hindlimb that mediates oxygen uptake, and thus thermogenesis, was observed. This vanilloid receptor, that is, the transient receptor potential vanilloid receptor-1 (TRPV1), is expressed in sensory neurons, the brain and various non-neuronal tissues, and is also involved in the pain pathway.74 Different polymorphisms for the TRPV1 receptor and UCP2 promoter region seem to be of importance in the therapeutic response toward capsinoid treatment. The TRPV1 Val585Ile polymorphism is associated with more abdominal fat loss compared with the Ile/Ile variant. This might explain the variability in outcomes between individuals.
Safety of capsaicin administration
Ingredients for obesity management are tea, caffeine and capsaicin, as they increase daily EE with 4–5% (=300–400 kJ) without increasing energy intake and counteract the decrease in metabolic rate during weight loss. Studies have shown that these ingredients are useful in losing weight or preventing weight regain after weight loss. These ingredients activate the SNS, which is involved in the regulation of energy balance. Evidence is present with respect to sensitivity of SNS to positive energy balances. In animals, SNS activation is a key element of the counter regulatory response to excessive food intake in heart and brown adipose tissue, and SNS activation is an important aspect of the response to overfeeding. SNS activation increases thermogenesis and wastes excess energy as heat, and thereby compensates for surplus energy intake. The result is the prevention of body weight gain.
Nevertheless, certain conditions are required before these tools are efficient. For instance, capsaicin is effective in principle, yet it requires a strong compliance that is not feasible yet. As mentioned, the CH-19 Sweet may be the solution for the compliance problem. Catechins and caffeine in tea, that inhibit catechol O-methyl-transferase and phosphodiesterase, have a bitter taste. Again compliance seems to be a problem, as people prefer different tastes. Furthermore, it has been shown that a GT–caffeine mixture is only efficient in low habitual caffeine consumers24 and that proteins which also improve WM, through thermogenesis, fat oxidation, sparing fat-free mass and satiety, have no synergistic effect with GT when administered simultaneously.46 However, caffeine, tea and capsaicin can until now be considered as relatively safe.
More studies are focusing on administering a combination of these bioactive ingredients in order to obtain a higher efficiency than when supplied separately. Reinbach et al.,84 for instance, showed a decrease in energy intake after administering a combination of capsaicin and GT or CH-19 Sweet pepper. Twenty-seven subjects participated in a study with a crossover design and were randomized to 3 weeks of negative and 3 weeks of positive energy balance, during which they received a combination of thermogenic ingredients. Subjects reduced their energy intake the most during positive energy balance after administering a combination of capsaicin and GT or CH-19 Sweet pepper. However, hunger was most suppressed and satiety was most enhanced after GT and capsaicin during negative energy balance compared with positive energy balance. The authors conclude that thermogenic food ingredients have energy intake reducing effects when used in combinations, and in positive energy balance.84 Belza et al.85 supplied a combination of GT extract, capsaicin, tyrosine and calcium for a period of 7 days. An increase of approximately 200 kJ (2%) in thermogenesis was seen after this period. A failure of synergism between GT and protein suggests that a combination of bioactive ingredients is not always a key to success. Furthermore, we hypothesized previously that genetic predisposition has an important role in whether or not bioactive ingredients efficiently increase thermogenesis. Studies with functional foods report great intra-variability between subjects concerning effects on satiety and EE. With respect to GT, different polymorphisms for the COMT enzyme exist. Allele frequencies show that the more favorable polymorphism is highly abundant in Asians, in contrast with Caucasians where only a minority possesses this polymorphism. Capsaicin may also have a similar mechanism that underlies their effects. As earlier mentioned, the TRPV1 Val585Ile polymorphism, a different genetic variant for the TRPV1 receptor, is associated with more abdominal fat loss compared with the Ile/Ile variant after capsiate treatment.81 It is hardly any coincidence that ingredients such as tea and capsaicin are very common in Asia and originate from this region. Asians seem to be more adapted to these ingredients as they are part of their daily lifestyle. Thus far, obesity does not seem to be a problem in this region at least not for the people who stick to the traditional diet. This means that thermogenic ingredients can be used as functional foods, and that they prevent a positive energy balance and obesity, when the right terms are met.
Ingredients for obesity management, including caffeine, capsaicin and different teas such as green, white and Oolong Tea, have been proposed as strategies for weight loss and WM, as they may increase EE (4–5%), fat oxidation (10–16%) and have been proposed to counteract the decrease in metabolic rate that is present during weight loss. Daily increases in thermogenesis of approximately 300–400 kJ can eventually lead to substantial weight loss. However, it becomes clearer that certain conditions have to be met before thermogenic ingredients yield an effect, as intra-variability with respect to body weight regulation has been shown between subjects. Taken together, these functional ingredients have the potential to produce significant effects on metabolic targets such as satiety, thermogenesis and fat oxidation. A significant clinical outcome sometimes may appear straightforwardly but also depends very strongly on full compliance of subjects. Nevertheless, thermogenic ingredients may be considered as functional agents that could help in preventing a positive energy balance and obesity.