Caffeine is one of the most commonly used ingredients in fat loss supplements. It occurs naturally in the leaves, seeds, or fruits of more than 60 different plants including cola nuts, mate leaves, and guarana paste. It is commonly found in coffee and chocolate, and is often used as a flavoring agent in cola beverages.Caffeine exerts effects through a number of different mechanisms.
The primary actions of caffeine are it stimulates the central nervous system and amplifies lipolysis. Lipolysis is controlled by an enzyme called hormonesensitive lipase (HSL). This enzyme exists in an inactive and active form. To activate HSL, another enzyme, adenylate cyclase, converts ATP into cyclic-3′, 5 ‘-AMP (cAMP) Cyclic-AMP then activates cAMP-dependent protein kinase which in turn phosphorylates HSL, thus activating the enzyme. The active form of the enzyme is responsible for cleaving the FFA off of the glycerol backbone of the triacylglycerol molecule. The FFA is then released into the bloodstream. Lipolysis ceases when cAMP is degraded to 5′ AMP by phosphodiesterase, thus becoming inactivated. Therefore, it stands to reason that any process which maintains cAMP levels will prolong the life of the active form of HSL and consequently lipolysis.
Caffeine and other methylxanthines inhibit phosphodiesterase activity. Caffeine is thus able to prolong the responses of cAMP by slowing the degradation of this messenger. Therefore, lipolysis continues for a longer period of time resulting in more FFAs being released to the bloodstream. Several studies have been conducted in animals and humans regarding the effectiveness of caffeine.
In Vitro Studies
In vitro studies allow scientists to determine the possible mechanism of action of a particular substance on metabolism. Research on caffeine, as discussed previously, shows us that caffeine inhibits phosphodiesterase activity and that this leads to an increase in adipose tissue lipolysis, a catabolic process. For a cell to carryon both catabolic and anabolic processes at the same time is difficult. The purpose of adipocytes is to store fat. The adipocyte can use fatty acids or glucose for triacylglycerol synthesis. In the case of glucose, the cell must first convert the glucose into fat through a process called lipogenesis. However, if lipolysis is going on, it is not possible for the cell to perform lipogenesis. Steinfelder and Petho-Schramm have demonstrated that caffeine inhibits glucose transport into rat adipocytes.
In addition to affecting adipose tissue, caffeine also affects brain tissue. Some of its effects in the brain will be discussed in the section on adverse reactions, however, other effects of caffeine in the brain may aid in the stimulation of lipolysis. The anterior pituitary gland is responsible for growth hormone (GH) production and secretion. Growth hormone, in addition to stimulating glucose and amino acid uptake, also stimulates lipolysis. Therefore, GH can increase fatty acid oxidation. In vitro research in cultured rat pituitary cells suggests that caffeine stimulates growth hormone secretion. This increase is more than likely caused by the inhibition of phosphodiesterase.
As in many cells, cAMP acts as a second messenger, which stimulates a number of metabolic pathways inside a cell. In this case, caffeine’s effect on phosphodiesterase results in an increase in GH secretion. It remains to be determined whether the oral consumption of caffeine stimulates GH secretion in humans, and if it does, whether the increase in GH is significant enough to alter lipolysis . Some insight into this question will be provided when animal and human research is discussed.
When the HSL is working at cleaving the fatty acids off of the glycerol backbone of the triacylglycerol molecule, glycerol is released into the circulation along with the three FFAs. Although not related to lipid oxidation at the muscle, the body needs to do something with the glycerol, which may enter glycolysis for oxidation or gluconeogenesis. In addition to stimulating lipolysis, caffeine also stimulates gluconeogenesis, or the making of glucose in the liver. Caffeine added to the suspensions of rat hepatocytes resulted in a two-fold increase in gluconeogenesis. The resulting increase in glucose produced by this pathway would then be used to maintain blood glucose levels or act as a precursor for liver glycogen. The increase in gluconeogenesis is likely due to the increase in the intracellular calcium concentration associated with caffeine.
The affect of caffeine on growth hormone secretion in animals is not as clear as the in vitro work. Work from two different laboratories has produced conflicting results. One lab has reported that caffeine injection results in a lowering of GH and thyroid hormones. Another lab reported that GH levels were increased following a single injection of caffeine. Following 10 days of caffeine injection, GH levels were still elevated but not to the extents that were observed following the initial injection. The differences between the two studies could be attributed to the age of the rats used. Clozel et al. used 5-day-old rats while Spindel et al. used older rats. This lends support to human research showing an age effect of caffeine.
In addition to affecting GH, caffeine influences catecholamine release from chromaffin granules in the adrenal medulla. Catecholamines can also stimulate lipolysis. Catecholamine biosynthesis begins with the amino acid tyrosine. Tyrosine is hydroxylated to dopa by tyrosine hydroxylase, which is the rate-limiting enzyme in catecholamine biosynthesis. Tyrosine hydroxylase appears to be regulated by cAMP-dependent protein kinase.
Therefore, caffeine may have the same effect on catecholamine biosynthesis as it does on lipolysis. That is, caffeine may prolong the activity of tyrosine hydroxylase by inhibiting phosphodiesterase. Furthermore, the release of catecholamines is calcium dependent and, caffeine is able to increase intracellular calcium levels through the release of calcium from intracellular stores and by increasing the entry of calcium from extracellular stores .
Though the effect of caffeine on hormones in animals is not all that clear, caffeine’s effect on lipolysis is clear. Numerous studies have reported that caffeine increases lipolysis in laboratory animals. Furthermore, research indicates that caffeine results in a more rapid loss in fat mass in exercised rats compared to rats that did not receive caffeine but still exercised.
Caffeine research in humans has produced some mixed results with positive results probably depending on the age, sex, and weight of the subject, and also the prior use of caffeine by the subject.
The effect of caffeine supplementation on resting metabolic rate and thermogenesis has been studied in the lean, obese, postobese (following weight loss), and young and old . Metabolic rate and/or thermogenesis increases with caffeine consumption in all populations and is dose dependent but, fat oxidation appears to increase only in lean individuals. Obese and older adults appear to have a blunted response to caffeine in regard to an increase in fat oxidation. There could be a number of reasons why the lean and obese respond differently to caffeine.
One reason could be the way caffeine is metabolized by the body. However, Caraco reported that obesity minimally alters caffeine pharmacokinetics and that this small alteration should not necessitate any significant dosage modifications. The differences among the populations may be due to the form in which caffeine was consumed. The studies that reported a difference between lean and obese individuals used coffee as the form of delivery.
Research by Graham et al has reported that there is a blunted catecholamine response during exercise following coffee consumption when compared with pure caffeine consumption. The study by Arciero that compares young and old men used pure caffeine. The other factor that could have influenced the results was the varying amount of caffeine used.
As in animals, caffeine also alters the plasma levels of certain hormones. Caffeine has repeatedly been shown to increase catecholamine levels Furthermore, the increase in catecholamines appears to be dose dependent.
Additional research indicates that a single dose of caffeine (500 mg) may also elevate growth hormone and tri-iodothyronine (T3 ) in men, but not women As discussed above, the caffeine-associated increase in growth hormone could further increase lipolysis and fat oxidation. Tri-iodothyronine is a thyroid hormone that increases resting metabolic rate and amplifies physiological signals responsible for stimulating lipolysis and fat mobilization.
Safety and Toxicity
Although it would appear that caffeine works well as a fat loss supplement, it has negative side effects. Caffeine has been reported to elevate arterial blood pressure and heart rate. Furthermore, it results in diuresis and increased gastric secretion, the latter of which can lead to loose bowels and possibly diarrhea at higher dosages.
Chronic caffeine ingestion is associated with a decrease in cerebral blood flow and an increase in mean arterial pressure Six days of chronic caffeine use resulted in the loss of the acute effects on mean arterial blood pressure, but not on blood flow. This indicates that there may be a development in peripheral tolerance but not central tolerance.
The headaches associated with caffeine withdrawal, experienced by some people, would be difficult to explain based on this research. The physiological effects of caffeine appear to last about 4 days.
Acute toxicity is characterized by hematemesis, tachycardia, hyperventilation, hyperglycemia, ketonuria, hypokalemia, and metabolic acidosis. Although deaths have been associated with excessive caffeine intake, the overdose of caffeine is rare because of the spontaneous and recurrent vomiting associated with the intake of toxic levels of caffeine. The LD (the lethal dose for half the subjects) of caffeine has been estimated to be between 150 and 200 mg/kg.
A dose of caffeine that results in blood levels that exceed 100 µg/mL is considered lethal, although acute toxicity begins at blood levels of 30 to 50 µg/mL A typical cup of coffee contains roughly 100 mg of caffeine and can increase blood caffeine levels to 1-2 µg/mL Several deaths have been associated with too much caffeine consumption, the most recent was a 22-year-old female who overdosed on diet pills. A serum toxicology report indicated that her blood levels were in the range of 1500 µg /mL .