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Paper text:
obesity has rapidly become a leading cause of death without a foreseeable resolution in the near future .
most clinicians believe the combination of food overconsumption with sedentary lifestyle synergistically promote weight gain and obesity .
the importance of restrictive dietary practices in combination with physical activity are of undeniable importance for weight loss and general health [ 1 , 2 ] ; however , the role of genomics and corresponding interactions with dietary and exercise practice still remain largely ill - defined as the field is still in its infancy .
a variety of therapies are currently available to combat obesity ; however recent trends in obesity prevalence provide strong evidence that current interventions are insufficient to effectively slow the development of obesity and related comorbidities [ 13 ] .
the role which food chemicals and dietary components may play in obesity therapeutics is increasing interest . in obesity research ,
several classes of chemicals including methylxanthines , polyphenols , capsaicin ( capsaicinoids / capsinoids ) , polyunsaturated fats , and many other components found in food have shown some promise in promoting a metabolic advantage for weight loss [ 4 , 5 ] . as a result of preliminary data supporting
some of the aforementioned ingredients , producers of commercially available dietary supplements often include one or many of these components in their products .
dietary supplements are sold for a variety of purposes , including weight loss , and many ingredients are promoted specific benefits such as increased thermogenesis .
dietary supplements are unique because unlike pharmaceutical agents , they do not require close regulation of content , function , or safety prior to consumption by humans   and are generally not recommended by healthcare professionals . because of limited regulation , it is not uncommon for single ingredients to be promoted for a promiscuous variety of unsubstantiated functions and health benefits . although subjected to limited regulation , it is mandated that all dietary supplements be marked with a disclaimer stating the lack of support by the fda for all claims .
supplements sold as thermogenic products for weight loss and/or energy augmenters are often promoted to cause rapid weight loss , often times independent of calorie restriction or physical activity . despite resistance from healthcare professionals ,
consumer interest in dietary supplements continues to surge . according to nhanes questionnaire data from roughly 12,000 participants ,
use was most common among 2030-year - old participants , and more common in women than in men .
interestingly when asked to select the motivating factor for supplement consumption ,  weight loss  or 
get more energy  were reported as the motivation for approximately 14% of participants , both of which were also more common in women participants .
this work seeks to summarize current research evaluating commercially available dietary supplements sold as stimulators of thermogenesis and increased metabolic rate leading to weight loss .
of the available dietary supplements marketed for weight loss , many contain a blend of ingredients that includes caffeine .
caffeine has previously been shown to dose - dependently heighten resting energy expenditure in adult humans , both normal and overweight [ 5 , 914 ] . despite some conflicting data
, it is generally accepted that caffeine effectively stimulates the central nervous system and increases metabolic rate in humans [ 1416 ] .
caffeine functions through inhibition of phosphodiesterase ( pde ) and through stimulation of adenosine receptors , leading to accumulation of intracellular 3,5-cyclic - adenosine monophosphate ( camp ) which is metabolically excitatory for cells [ 11 , 12 , 14 ] . like caffeine , stimulators of 2-adrenergic receptors such as
ephedra / ephedrine have been another primary component found in supplemental thermogenic products [ 9 , 11 , 14 ] . following the restriction of ephedra use ,
similar chemical analogs such as synephrine from bitter orange extract became widely accepted replacements [ 1720 ] .
2-adrenergic receptor agonists work to increase camp biosynthesis , while caffeine inhibits the breakdown of camp by pde .
additionally , salicylates inhibit prostaglandins further allowing the accumulation of camp . taken together , caffeine , 2-adrenergic receptor agonists and salicylates function to synergistically increase camp accumulation and metabolic rate .
several other dietary stimulators of metabolism are thought to function by augmenting the accumulation of camp .
green tea extract is rich in polyphenols and is heavily promoted for health benefits including increased metabolism [ 4 , 1214 , 2128 ] .
epigallocatechin gallate ( egcg ) , epigallocatechin ( egc ) , epicatechin gallate ( ecg ) , and epicatechin ( ec ) are believed to cause most of green tea 's beneficial effects .
other teas such as black tea , thearubigins , and theaflavins share similar effects to those found in green tea [ 4 , 29 ] .
green tea extract appears to offer some thermogenic effect when coupled with caffeine resulting in increased energy expenditure [ 14 , 22 , 30 ] .
in contrast , isolated green tea polyphenol ingestion independent of caffeine does not appear to increase metabolic rate ; however it does increase indicators of fat metabolism in some populations [ 14 , 22 , 30 ] .
green tea is purported to function by inhibiting the degradation of 2-adrenergic receptor agonists such as norepinephrine by the enzyme catechol o - methyltransferase ( comt ) , thereby increasing intracellular camp [ 4 , 12 ] .
again , the combination of green tea polyphenols with caffeine cause a synergistic effect further increasing camp . recently , the effects and mechanisms of green tea extract in human metabolism were reviewed and it was suggested that the mechanism of comt inhibition is possibly a product of in vitro experimental conditions , because comt inhibition experiments have yet to identify a specific catechin inhibitor , or determine if the active polyphenol is an inhibitor , a substrate of comt , or a combination .
additionally , the mechanisms of the hypothesized downstream effect of comt inhibition resulting in heightened fat metabolism have yet to be elucidated experimentally .
in addition to comt inhibition , it is theorized that effects of green tea extract are also a function of metabolic gene activation .
specifically , green tea may function to inhibit adipogenic genes such as peroxisome proliferator - activated receptor ( ppar ) and sterol regulatory element binding protein-1c ( srebp-1c ) and increase the expression of genes that increase energy expenditure and mitochondrial biogenesis including nuclear respiratory factors ( nrf ) , mitochondrial uncoupling protein-3 ( ucp3 ) , peroxisome proliferator - activated receptor ( ppar ) , and peroxisome proliferator - activated receptor  coactivator-1 ( pgc-1 ) , leading to increased oxidative and metabolic capacities .
another common constituent of thermogenic products is the capsaicinoids / capsinoids , components found in spicy foods such as chili pepper and cayenne [ 32 , 33 ] .
available data suggests that supplemental capsaicinoids / capsinoids effectively increase resting energy expenditure , although findings have been inconsistent [ 3234 ] .
capsaicinoids are believed to function by increasing catecholamine release , heightening sensitivity to circulating catecholamines , or a combination thereof .  
figure 1 summarizes the proposed mechanisms of the abovementioned individual ingredients commonly found in commercially available thermogenic products .
several previous investigations have identified that commercially available products increase resting energy expenditure in a variety of subjects , most frequently using young healthy subjects ( table 1 ) .
most commonly these products contain several of the following : caffeine , green tea , capsaicin , and catecholamine - like compounds ( synephrine ) .
in general , most investigations evaluated changes in energy expenditure within 6 hours of consumption .
while the magnitude of the individual supplement 's effect on energy expenditure seems to vary depending on the ingredients consumed , the increase in energy expenditure is similar to previous observations using individual ingredients such as caffeine , ranging from 50 to 200  k  cals per hour immediately following ingestion .
although this increase is experimentally significant , it must be stressed that the effect is time - dependent and energy expenditure appears to return to basal levels 6 hours following consumption .
previous acute ( 24 hours or less ) investigations with caffeine alone or green tea with caffeine showed approximately a 4% increase in 24 hour metabolic rate [ 5 , 10 , 12 , 14 ] which approximates the increases seen with selected thermogenic products .
extended treatment for up to 8 weeks has also shown increased resting energy expenditure , suggesting that regular green tea consumption with select stimulants can continuously cause an increase in metabolism [ 35 , 36 ] . despite evidence that several of the single ingredients previously described have been shown to increase metabolic rate , there is some question about the efficacy of advertised dietary products for weight reduction .
hasani - ranjbar and colleagues selectively identified dozens of studies which implicate natural products in the reduction of body weight in humans .
the investigations reviewed ingredients frequently found in dietary supplements including caffeine , ephedra , and a variety of herbal agents , many of which function in part as antioxidants .
these studies included experimental designs lasting from as little as 4 weeks to up to 9 months without controlling for exercise and/or concurrent energy restriction .
in general , there appears to be some evidence that thermogenic products may partially aid in weight loss , although it is difficult to identify the magnitude because of between - study variables .
one possible contributor to discrepancies within the literature regarding efficacy of individual ingredients is experimental variability .
multiple confounds exist in energy expenditure measurements such as duration of measurement , type of analytical and measurement software , duration of measurement after ingestion of stimulant , and the amount of purported metabolic stimulator consumed .
an additional issue is that much of the original measurements were conducted several decades ago .
moreover , significant biological differences between demographics may also contribute to varied response across similar studies .
proprietary blends found within dietary supplements have numerous issues that are not encountered when testing pharmaceutical grade single chemicals ( such as caffeine ) .
for example , dietary supplements may vary in content from one lot to the next , suggesting some batches function better than others .
additionally , supplements are not required to third - party test products for purity and content , which allows for the possibility that nonlisted ingredients are included and ingredients that are purportedly included are missing .
such inconsistencies would likely inflate the variability of experimental measurement , contributing to inconsistencies in the reported effects of dietary supplements .
perhaps the most significant limitation to commercially available dietary supplements is the near - complete absence of scholarly evidence supporting individual product safety and efficacy .
another interesting and significant variable worth discussing is the matter of funding for research on dietary supplements .
multiple articles disclose that funding is contributed by the companies which market the product for retail purposes .
this is not surprising because cost of biological research continues to increase while funding opportunities remain limited ; therefore it is logical that select companies have outsourced primary research opportunities to the university setting .
surprisingly , many dietary supplements advertise one or multiple nonbiased studies illustrating efficacy of their product ; however often times these studies have not been systematically peer - reviewed or readily shared with the scientific community making the original research difficult to locate .
in addition , identification and tracking of adverse events with the majority of studies would not meet requirements for similar pharmaceutical agents .
of the known adverse effects , dry mouth , insomnia , nervousness , palpitations , headache hypertension , arrhythmias , myocardial infarction , stroke , and seizures have been linked to consumption of ingredients such as caffeine and ephedra , suggesting a major need for further safety evaluation prior to consumption [ 6 , 7 ] .
lastly , along with limited evidence of whole - body efficacy and safety , there is inadequate evaluation of the molecular effects of commercially available dietary supplements .
our lab previously demonstrated that select dietary supplements containing a variety of ingredients could effectively increase skeletal muscle metabolism and mitochondrial content in vitro ; however additional information is required to adequately describe cell- and tissue - specific effects of thermogenic products [ 45 , 46 ] .
increasing obesity prevalence and consumer interest in thermogenic dietary supplements support the need for further research of these and other supplement ingredients . from the available evidence , it appears that commercially available dietary supplements advertised to stimulate metabolism have the propensity to increase metabolic rate . despite significant increases in resting energy expenditure ,
it is doubtful that commercially available thermogenic products stimulate metabolism more than consumption of food products containing equivocal content of caffeine / stimulants and/or polyphenols .
moreover , it should be mentioned that increases in metabolism induced by food or dietary supplement are small , contributing only subtly to metabolic rate .
additional research is necessary to identify the precise mechanisms by which commonly consumed ingredients function to alter energy expenditure and what corresponding molecular adaptations may develop .
commercially available dietary products advertised to promote weight loss are an underresearched but heavily purchased commodity in the united states . despite only limited evidence , interest in dietary supplements 
 continues to increase . 
 this work uniquely summarizes the current evidence evaluating the efficacy of several over - the - counter thermogenic products for their effects on resting energy expenditure . currently , there is some evidence suggesting dietary products containing select ingredients can increase energy expenditure in healthy young people immediately following consumption ( within 6 hours ) . 
 it is unclear if supplement - induced increases in metabolic rate provide additional benefit beyond that provided by dietary constituents that contain similar ingredients . 
 it is also unclear if dietary supplements are effective for weight loss in humans .