Caffeine (1, 3, 7-trimethyl-xanthine)
Caffeine is the most popular drug consumed worldwide . Approximately 80% of the world’s population consumes a caffeinated product every day, and 90% of adults in North America consume caffeine on a daily basis . Caffeine is a naturally occurring alkaloid that is found in varying quantities in the beans, leaves, and fruits of more than 60 plants. Some common sources of caffeine are the kola nut, cacao bean, yerba mate, and guarana berry. However, roasted coffee beans and tea leaves (Camellia sinensis) are the world’s primary sources of dietary caffeine , .
Caffeine is rapidly absorbed through the gastrointestinal (GI) tract and moves through cellular membranes with the same efficiency as when it is absorbed and circulated to tissue . Caffeine is metabolized by the liver, and through enzymatic action results in three metabolites: paraxanthine (1, 7-dimethyl-xanthine), theophylline (1, 3-dimethyl-xanthine), and theobromine (3, 7-dimethyl-xanthine) , . Paraxanthine is the major metabolite and accounts for 84% of the identified products . Elevated levels of caffeine appear in the blood stream within 15–45 min of consumption, peaking around 60 min post-consumption. As a lipid soluble compound, caffeine freely crosses the blood brain barrier , and, therefore, affects neural function. Table 1 shows that there are many beneficial effects of caffeine on the human body, and many of these effects are attributed to energy balance.
Caffeine increases the excitability of the sympathetic nervous system (SNS) . The SNS is considered as an essential component of the autonomic nervous system, playing an important role in maintaining energy homeostasis through hormonal and neural control. The SNS has been described as a complex regulatory system involving direct effects of sympathetic nerves which innervate most body tissues, as well as indirect effects via catecholamine (CA), epinephrine, and to a lesser extent norepinephrine, which are released into the blood from the adrenal medulla . The activation of SNS has been shown to suppress hunger, enhance satiety, and stimulate EE, in part by increasing fat oxidation .
The intracellular signal, which produces increased lipolysis, heat production in skeletal muscle, and putative satiety signals in the liver, is dependent on the production and presence of cyclic adenosine monophosphate (cAMP). Increased cAMP response is short-lived, because it is rapidly degraded by phosphor-diesterase (PDE). The intracellular signal can be sustained for a longer period of time by the inhibition of PDE by methylxanthines (e.g. caffeine). Caffeine also antagonizes the effect of adenosine in the presynaptic nerve terminals, by reversing the adenosine-mediated inhibition of the release of CA ,  (see Figure 1).
Overweight and obesity
Overweight and obesity represent a rapidly growing worldwide threat to human health. Globally, over one billion adults are overweight, and 300 million are obese . Between 2009 and 2010 more than 36% of adults (20 years and older) in the US were considered to be obese and 69% were overweight or obese .
Obesity is an accumulation of body fat over the desired range, and at ages 20–40 years obesity is a condition where men have over 25% fat (desirable range: 8%–19%) and women over 39% fat (desirable range: 21%–33%) . The increased occurrence of overweight and obesity is commonly associated with increased consumption of calorie-dense foods with poor nutritional value, and with little or no physical activity , .
Overweight and obesity constitute a major risk for a number of serious diseases, including hypertension, dyslipidemia, type 2 diabetes mellitus, cardiovascular disease, gallbladder disease, stroke, osteoarthritis, various cancers, and sleep apnea .
As obesity is caused by an imbalance between energy intake (EI) and energy expenditure (EE) , it is logical to assume that a negative energy balance is required to bring about weight (mostly fat) loss, which can be achieved by either decreasing EI or increasing EE .
Obesity and the sympathetic nervous system
Previous studies have demonstrated that SNS activity modulates the resting metabolic rate (RMR), which is the largest constituent of daily EE . Astrup et al.  hypothesized that a low EE phenotype predisposes individuals to weight gain and to obesity. Low EE usually results from a low RMR, physical inactivity, or from a combination of both, and has been shown to precede body weight gain in infants, children, and adults . Results of a meta-analysis conducted on 12 studies found that RMR values in lean post obese subjects were 3%–5% lower than the values measured in lean subjects who had never been obese .
Decreased responsiveness to SNS may lead to decreased SNS activity, and therefore to the development of obesity. Decreased responsiveness may result from polymorphisms in the gene encoding for various types of adrenoceptors and uncoupling proteins (UCPs) . Several studies reported that a variant in the gene encoding for the β3-adrenoceptor has been linked to obesity and diabetes, and particularly to a lower metabolic rate .
There is growing evidence which demonstrates that an increase in sympathetic and thermogenic activities is associated with reduction of food intake. Therefore, it is reasonable to assume that obesity may also be caused by an increase in food intake (EI) resulting from reduced sympathetic activity , manifesting the important role of SNS in regulating both EE and EI.
Caffeine and energy expenditure
Numerous studies described the beneficial effect of caffeine on EE , , , , , , , , , , . Two studies examined the influence of caffeine on the RMR in young (20–40 years) physically trained and untrained men. Leblanc et al.  conducted a study on eight trained and eight untrained young males. Both groups were instructed to consume one cup of coffee containing 4 mg/kg caffeine after an overnight fast, which resulted in an increase of RMR values in both groups but a greater increase of RMR in the trained subjects (p<0.05). This effect was also associated with a greater increase in plasma free fatty acids (FFAs) and a greater fall in the respiratory quotient, indicating enhanced lipid oxidation following caffeine consumption in trained subjects. Poehlman et al.  studied 14 trained and 10 untrained men. The subjects were supplemented with 300 mg of caffeine after an overnight fast, leading to an increase of RMR in both groups, but in contrast to Leblanc et al.’s  results, a greater increase was observed in the untrained subjects (p<0.05). It is unclear why the two studies produced contradictory results. One possible explanation may be related to the protocols of the two studies, which were not conducted in a double-blind design, and did not use a placebo. In addition, Leblanc et al.  used coffee and Poehlman et al.  used pure caffeine. Caffeine is more powerful when consumed in an anhydrous state (capsule/tablet/powder), as compared to prepared coffee .
One study investigated the combined effect of exercise and caffeine supplementation on enhancing acute energy deficits and manipulations to substrate metabolism, compared with the effect of just exercise . Fourteen recreationally-active participants aged 18–45 years completed a resting control trial (CON), a placebo exercise trial (EX), and a caffeine exercise trial (EX+CAF, 2×3 mg/kg of caffeine 90 min before and 30 min after exercise). Trials were 4 h in duration with 1 h of rest, 1 h of cycling at ~65% of VO2max or rest, and a 2 h recovery. Gas exchange, appetite perceptions, and blood samples were obtained periodically. Two hours after exercise participants were offered an ad libitum test meal, where energy and macronutrient intake were recorded. EX+CAF resulted in significantly greater EE and fat oxidation compared to EX (+250 kJ; +10.4 g) and CON (+3126 kJ; +29.7 g) (p<0.05). A trend for reduced energy and fat intake compared to CON (–718 kJ; –8 g) (p=0.055) was observed. Consequently, EX+CAF created a greater energy deficit (p<0.05). The implications of these results for weight loss or maintenance over longer time periods in overweight/obese populations require further investigation.
Several studies investigated whether the beneficial effects of caffeine on EE are related to body weight , , , , . Previous studies have found that the pharmacokinetics of caffeine is different between lean and obese subjects , , , . For example, Kamimori et al.  examined the effect of obesity on the pharmacokinetics of caffeine in six college males [three lean (LW) and three obese (OW)]. Each subject received either caffeine (oral, 5.83 mg/kg lean body mass) or a placebo (50 mg citrate) prior to 3 h of seated rest. The pharmacokinetics analysis indicated that at rest, the OW had a significantly higher absorption rate constant (Ka) compared with that of the LW (0.0757 vs. 0.0397 min–1, OW vs. LW, respectively), a lower elimination rate constant (Ke, 0.0027 vs. 0.0045 min–1, OW vs. LW, respectively), and longer serum half-life (t½, 4.37 vs. 2.59 h, OW vs. LW, respectively) (p<0.05). The authors suggested that there is a difference in regional blood flow between obese and lean subjects. These results are in agreement with Bracco et al.’s  findings that obese women excrete more theobromine, theophylline, and paraxanthine than lean woman, suggesting an impairment of the final degradation of dimethylxanthines into monomethylxanthines – the end products of caffeine metabolism. Previous research found that the adipose tissue of obese rats had a reduced capillary density and a slower flow rate through the capillaries in comparison to the adipose tissue of lean rats. Other studies reported that the FFA response to caffeine in resting obese humans was delayed , , probably as a result of a decrease in the rate of caffeine delivery to the adipose tissue, which leads to a decreased sensitivity to lipolysis stimuli. These results support the finding of other studies ,  that obesity results in modifications in regional blood flow and thus in the distribution and clearance of some drugs.
These results reported that there are differences between OW and LW subjects in the pharmacokinetics of caffeine and also in lipolysis under the influence of caffeine. Thus it is interesting to examine whether there were also differences between OW and LW subjects in the effect of caffeine on EE.
Acheson et al.  investigated the effects of coffee (~4 mg/kg caffeine) on the metabolic rate and substrate utilization in LW (n=7) and OW (n=6) individuals (gender was not specified). Resting metabolic rate increased significantly in LW (12%±3%, p<0.01) and in OW (10%±2%, p<0.05), with no significant difference between the groups. However significant increases in fat oxidation were observed only in LW, probably due to the low sensitivity to lipolysis stimuli in obese humans . These results are in agreement with the results of Bracco et al. , who studied 10 lean and 10 obese women. After consumption of coffee (4 mg caffeine/kg ideal weight), lipid oxidation was higher in LW (29%, p≤0.0001) compared to OW (10%, p≤0.03). The authors reported that the total daily energy expenditure was higher in the LW (7.6%±1.3%, p<0.0005) compared to OW (4.9%±2%, p<0.005). This study also investigated the influence of coffee consumption on the urinary methylxanthine excretion, and it was found that there was greater dimethylxanthine excretion in obese women. This demonstrates an impairment of the final degradetion of dimethylxanthines into monomethylxanthines, the end products of caffeine metabolism. These results agree with those in the study of Kamimori et al. , which described a longer half-life and a slower elimination rate constant for caffeine in obese subjects.
Jung et al.  and Yoshida et al.  conducted their studies on obese and lean women. The two studies used 4 mg/kg of caffeine and found a significant increase in EE values in each group after caffeine consumption, however, no significant differences were observed between lean and obese women. It should be noted that as most of the studies cited earlier reported results on female subjects, there is a need to conduct similar studies on LW and OW men.
Although many of the studies mentioned above suggest that caffeine consumption elicits different responses of lipolysis and EE in LW compared with OW, caffeine is reported to have positive effects on EE and lipolysis in OW, and therefore its use may be considered for weight loss , , . A possible mechanism by which caffeine affects EE is by intensification of CA secretion. CA binds to adipose cells, causing an increase of thermogenesis through an augmentation in thermogenic gene expression and a release of FFAs, which in turn brings about an increase in UCPs that produce heat in the mitochondria , . Kogure et al.  found that caffeine upregulates the expression of UCPs in brown adipose tissue and in skeletal muscles, which may contribute to thermogenesis in obese mice. Matteis et al.  studied two groups of morbidly obese patients (body mass index, BMI>40 kg/m2) who followed a hypoenergetic diet for 4 weeks (70% of EE). One of the groups (Ex) was given ephedrine and caffeine (20/200 mg, 3×daily), while the other group (C) received placebos. There was an increase in β3-adrenoceptor (CA target) in the white adipose tissue in the Ex group. These results support the potential use of β3-adrenoceptor agonists in the treatment of obesity.
Caffeine and energy intake
The effect of caffeine or coffee on EI was examined in various studies , , , , , . Some of these examine the combined effect of caffeine and other materials that suppress appetite. Yoshioka et al.  investigated the combination of caffeine and red pepper on 24 h EI ad libitum until satiety under conditions mimicking real life as closely as possible. Previous studies found that red pepper increases EE and decreases EI, and also that they contain capsaicin, which has a stimulating effect on energy and lipid metabolism. Yoshioka et al.’s  study was conducted on 8 healthy men aged 25±2.9 years (BMI range 20.7–26.8 kg/m2). Members of the experimental group were supplemented with red pepper powder in their food, and drank decaffeinated coffee with a dissolved caffeine supplement (200 mg). The control group did not receive red pepper and drank decaffeinated coffee (i.e. without caffeine). Prospective food consumption, appetite, hunger, fullness, and satiety were rated immediately before and after each appetizer, meal, desert snack, and drink by using a 150 mm visual analog scale (VAS). The addition of red pepper and caffeine significantly (p<0.05) decreased the cumulative energy (17% decrease) and macronutrient intakes (protein, lipid, and carbohydrate; 16.5%, 20.5%, and 15.5% decrease, respectively). There was a tendency for a lower appetite in the experimental group compared with the control group (53.7±26.3, and 64.4±27.6 mm, respectively; p<0.08). The authors attributed their findings to the combined effect of caffeine and red pepper, which led to increased SNS activity and a decrease in EI. In addition, adding caffeine and red pepper may have decreased the palatability of foods, which contributed to decreased EI.
The synergistic effect of caffeine with other material was also examined with nicotine. Jessen et al.  tested whether the anorectic effect of nicotine may be amplified by caffeine consumption. Twelve healthy men aged 24.3±3.1 (BMI 23.3±1.7 kg/m2) consumed six different caffeine (50 or 100 mg)/nicotine (1 or 2 mg) doses and a placebo provided in pieces of chewing gum during seven separate visits to the laboratory. Appetite-related parameters (hunger, fullness, and satiety) were assessed using VAS. Caffeine appeared to amplify the effects of nicotine on hunger and fullness, as a significant caffeine×nicotine×time interaction was observed in these scores (p<0.05). This response may be explained by the kinetics of maximal blood caffeine levels that were reached 15–120 min following consumption, and by the plasma caffeine half-life (t½) of 2.5–4.5 . Carter and Drewnowski  investigated the combined effect of caffeine with other materials: soluble fibers and green tea catechins. Previous research has shown that beverages containing soluble fibers can decrease EI, and food containing green tea catechins may contribute to the satiating power of foods and beverages. This study was conducted on 77 subjects (74 finished the trial; 40 males and 34 females), aged 18–45 years, in order to examine the satiating power of a beverage containing soluble fiber as well as a beverage containing similar nutritional fibers, caffeine, and green tea catechins. These two test beverages were evaluated in comparison to an equal-calorie control beverage as well as a no-beverage control condition. The no-beverage condition was associated with the highest hunger ratings and the lowest fullness ratings when compared to the other three beverage conditions. Of the three beverage conditions, the one containing the fiber, green tea catechins, and caffeine resulted in the lowest hunger and the highest fullness ratings.
It can be concluded from these studies that caffeine amplifies the anorectic effect of other materials, and that there is a higher degree synergistic effect when these are combined (e.g. caffeine and nicotine/red pepper/soluble fibers/catechine) compared with the individual effect of each.
Gender has an important effect on caffeine metabolism. Circulating levels of ovarian hormones influence the central effects of stimulant drugs in women . In addition, body responses to substances such as caffeine, nicotine, and alcohol differ between genders . Tremblay et al.  investigated whether a gender difference also exists in the short-term adaptation of EI following caffeine consumption. Spontaneous food intake was measured on two occasions in young men (n=10) and women (n=10) aged about 20 years. At the beginning of the sessions, subjects randomly consumed 300 mg of caffeine or a placebo, 30 min before they had free access to various foods. To facilitate the measurement of food intake, foods were proportionally weighed before each session using an analytical scale for solid foods and a measuring cup for the liquids. Following the ingestion of caffeine, EI was reduced by 21.7% in the men in comparison to their control situation (816±221 vs. 1043±209 kcal, p<0.05). On the other hand, caffeine had no significant effect on EI in the women. Previous studies have found gender differences in the response to factors influencing the SNS , , , , , , , . For instance, higher responses in blood pressure and CA to cold and exercise stress were recorded in men compared with women , , . This expression of a gender dimorphism in the short-term adaptation of EI to caffeine is consistent with previous findings , which showed that women tend to preserve their body energy stores longer than men in situations that stimulate their SNS when they are exposed to factors activating the SNS.
Bakuradze et al.  investigated the mechanisms involved in the effects of coffee consumption on body weight/composition, food intake, satiety, and DNA integrity in a 4-week double-blind randomized crossover intervention with 84 healthy subjects (46 males and 38 females) aged 25.6±5.8 years. Satiety levels were measured by plasma serotonin and ghrelin concentrations. The two molecules were found to play important roles in the regulation of hunger and satiety. In addition, increases in the secretion of serotonin by neuronal cells in the intestine in response to intraluminal stimuli reportedly reduce food intake , while increases in the secretion of ghrelin by gastric cells were found to stimulate appetite and food intake in rodents and humans . Coffee consumption (3×250 mL/day) was associated with a decrease in body fat over the study period (p<0.001). During the intervention, plasma serotonin levels increased (p<0.001), whereas plasma ghrelin levels decreased (p<0.001) relative to levels recorded during the preceding washout period. The coffee consumption was also associated with DNA-protective effects (p<0.001). These findings suggest that regular coffee consumption may provide health benefits by reducing EI and body fat, regulating satiety, and protecting DNA integrity.
The effect of caffeine on EI also was examined in nonhuman studies, in order to investigate the mechanism of the anorectic effects of caffeine. Racotta et al.  investigated the combination of corticotropin-releasing hormone (CRH) and the SNS with caffeine on food intake and body weight gain in rats. CRH and peripheral CA are significant anorectic agents, whose secretions are enhanced by caffeine. This study examined the potential involvement of CRH by treating rats with the CRH antagonist, α-helical-CRH, prior to an injection of caffeine. The implication of the SNS in the anorectic effects of caffeine was assessed by testing the effects of caffeine in rats after adrenal demedullation (medullectomy) and ganglionic blockade by hexamethonium (HEX). It was found that there was a significant (p<0.05) interaction effect of caffeine and α-helical-CRH on the food intake. In addition, the use of a CRH antagonist largely prevented the effects of caffeine on food intake of food-deprived rats. It was also found that there was no interaction effect of caffeine and medullectomy on food intake and body weight gain. There was no main effect of HEX and no caffeine-HEX interaction effect of food intake and body-weight gains. These results emphasize the role of CRH in the control of food intake. However, the SNS does not appear to be involved in the anorectic effects of caffeine, and the reasons for this remain obscure. It is plausible, that caffeine may lead to CRH effects on food intake that are independent of the SNS.
Other studies found no effects of caffeine on EI , . For example, Greenberg and Geliebter  examined the acute effects of caffeine, coffee, and decaffeinated coffee on perceived hunger and satiety and on blood levels of ghrelin, Peptide YY (PYY), and leptin on 11 healthy men. PYY is a gut hormone and one of the major anorexigenic gastrointestinal peptides. Leptin is a hormone that is synthesized predominantly by adipocytes and has been shown to decrease EI and increase EE. The subjects ingested 1 of 3 test beverages (6 mg caffeine/kg, coffee containing 6 mg caffeine/kg, or decaffeinated coffee) or a placebo and 60 min later all the subjects ingested glucose. Eight times during each laboratory visit, hunger and satiety were assessed by VAS, and blood samples were drawn to measure ghrelin, PYY, and leptin. Compared with the placebo, decaffeinated coffee yielded significantly lower hunger and higher plasma PYY (p<0.05). Caffeine in water had no effects on hunger or PYY. There were no significant beverage effects for ghrelin and leptin. These findings suggest that one or more noncaffeine ingredients in coffee may have the potential to decrease body weight; however, glucose ingestion did not change the effects of the beverages.
Caffeine seems to have an influence on the energy balance by increasing EE and decreasing EI, therefore, it can potentially be considered as a body-weight regulator. This article reviewed studies which demonstrate that caffeine can improve the energy balance when consumed in low-to-moderate doses (~3–4 mg/kg) by physically active or sedentary as well as obese or normal-weight men and women, and by laboratory animals. However, a few studies reported no effect of caffeine on EI , , and therefore the effect of caffeine on EI is still questionable and requires further, carefully controlled randomly designed studies.
Caffeine is associated with rising EE, and thus we suggest that caffeine may counteract the decrease in metabolic rate commonly occurring during periods of weight reduction. Furthermore, obese individuals with reduced thermogenesis in response to caffeine may experience difficulties in losing body weight with conventional treatment, and may require a very low-calorie diet, possibly controlled by treatment with a metabolic activator. Hossein et al.  found that a combination of caffeine treatment with a calorie-shifting diet could be an effective alternative approach to weight and fat loss, with small changes in RMR and improved tolerance of the subjects to the new diet. Interestingly, a recent study reported that those who maintain their weight loss consume more cups of coffee and caffeinated beverages compared with the general population sample . Nordestgaard et al.  reported that heavy coffee consumption was associated with a low risk of obesity, metabolic syndrome, and type 2 diabetes. Caffeine can be used as a regulator of weight control and in the prevention of comorbidities. Apparently, as caffeine consumption increases the risk of obesity and diabetes decreases. Further studies should investigate possible mechanisms for this effect.
Caffeine increases the EE and decrease the EI by SNS activation . The intracellular signal, which produces increased lipolysis, heat production in skeletal muscle, and putative satiety signals in the liver, occurs by the inhibition of PDE and also by increasing the UCPs , , . It has recently been demonstrated in an in vitro study that caffeine suppresses adipocytes differentiation by inhibition of C/EBPα and PPARγ expression, known as the main adipogenic transcription factors, and by promotion of the expression of negative regulators such as pre-adipocyte factor 1 and KLF2. Therefore, it is possible that caffeine influences weight loss also by inhibition lipogenesis .
It appears that there are certain situations in which the caffeine mechanism acts differently. The pharmacokinetics of caffeine is different in lean and obese subjects , , , . It was found that caffeine amplifies fat oxidation better in lean vs. obese women , . However there were no differences in the effects of caffeine on EE among overweight vs. normal weight women. Caffeine metabolism was found to be different between genders , , . Therefore, we suggest that a future study be conducted on a relatively large number of men to test whether the influence of caffeine on EE differs between obese and normal-weight men. In addition, some studies recruited women and men without differentiating them from each other. Due to the gender differences, in future studies, gender differences must be taken into account. Another important issue is sample size; most of the studies had only a small number of participants.
Another interesting finding was that the synergism between caffeine and other factors that increase the SNS/decrease the EI (exercise, red pepper, nicotine, soluble fiber, green tea) amplify the effect on EI , , , , . The implications of these findings for weight loss or maintenance over longer periods of time in overweight/obese populations await further investigations.
Racotta et al.  found that the CRH involved in the control of EI in rats worked in a way that was independent from the SNS. It was also found that the SNS was not involved in the regulation of food intake. The reason for this is unclear, but this finding is contradictory to other findings that the SNS does play a role in the control of the EI.
Another future direction could be the aspect of differences in gene expression. Some previous studies have examined the relationship between caffeine metabolism and genetics , , , , , , , . Most of them examined the relationship between coffee consumption and gene polymorphism of the caffeine receptor (A2A) or liver enzymes (cytochrome P450). A recent META analysis  provides current analyses of the relationship between habitual coffee consumption and genetic differences. Furthermore, an additional 5%–8% of the variance in RMR is accounted for by family membership . This strongly suggests that RMR is influenced by genetic factors. Therefore, future research can combine tests of caffeine on RMR with the measurement of gene expression. In addition, recent studies have examined the effect of maternal caffeine intake during pregnancy and risk of childhood obesity , , . It would be interesting to study how those genes are expressed in children whose mothers were exposed to a high level of caffeine during pregnancy.
Another possible direction for future research is the effect of caffeine or coffee on EE through mediation of gut bacteria. Several studies have found that drinking coffee causes a change in the composition of the intestinal population , , , . Recent studies have reported that gut bacteria affect EE , , and further studies are needed to test these effects.
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About the article
Published Online: 2016-11-08
Published in Print: 2017-01-01
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.