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Thermogenesis:
Deliberately Wasteful Energy?

By Tammy Thomas, RD, M.Sc., CSCS
First published at www.johnberardi.com, Jul 4 2003.

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Thermogenic aids, such as Muscle Tech’s “Hydroxycut”, Labrada’s “Charge,” or Biotest’s “Hot Rox” are variations of Ma Huang/ephedrine-based products that act as sympathomimetics, which are desired for their ability to melt the fat off bodies. The term ‘Thermogenics’ has become synonymous with fat burning, and products with this word on the label seem to sell themselves. But what does this word really mean? And where does all this biological “heat” that supposedly burns our body fat come from?

Be forewarned - the answer is not as easy as taking the pills!

To explain the body processes of thermogenesis, we’re going to have to travel from system physiology all the way down to subcellular physiology. Provided as a foundation, the review of basic metabolism and energy expenditure may seem painfully elementary to some of you and painfully complex to others. However, regardless, print this article, spend some time taking notes, and after investing a little time, you’ll have a pretty good overview of how the body produces heat and of the cellular and subcellular processes are involved in body composition optimization. Since this article is pretty technical, I'll understand if you if you’d rather bail out and just go read about how to get lean elsewhere on the site. Some of the other articles here will be a little more applied than this physiological discussion. But for those who choose to tough it out, kudos to you. You'll have a much greater understanding of how the body burns off nasty adipose tissue.

Thermoregulation

The hypothalamus is the temperature control center in the brain and it acts like a thermostat to regulate body temperature. Thermal receptors on the skin and the temperature of the blood stimulate the thermoregulatory center in the hypothalamus so that it can make the appropriate adjustments (1). The ways in which the body gains heat are through Basal metabolic rate (BMR), muscular activity, or the thermic effect of activity (TEA), hormones, the thermic effect of food (TEF) or diet-induced thermogenesis (DIT), and the environment.

Energy

A calorie is defined as the amount of heat that is required to raise 1 kg or 1L of water 1°C. When speaking about caloric content in food, the term kilocalorie is more commonly used. In other words, 1 kilocalorie (1 kcal) = 1000 calories (1). Different foods contain different amounts of caloric energy and I believe that food items provide different amounts of energy when combusted in pure oxygen (in a bomb calorimeter) versus while in the body. Reasons for this variability may be attributed to the energy states of the cells, the hormonal milieu, an individual’s fitness level, and genetics, to name a few.

The process of cellular respiration occurs as the body metabolizes food or ‘combusts’ fuel to provide energy for work. Therefore, understanding that our bodies are very similar to machines needing fuel to run helps us to recognize the importance of diet for physiological functions. The nutrients we ingest undergo a process similar to combustion within cells, and during the process of metabolism, energy released from fuel (food) combustion is conserved in the chemical reactions in the body. This energy is either released as heat (in exothermic reactions) or absorbed as energy for other reactions to take place (endothermic reactions). Ultimately, the goal of oxidative metabolism is the resynthesis of high-energy bonds that can be recharged for energy requiring processes in the body (2).

Oxygen from the environment is inspired, infused into tissues, and becomes available for intracellular oxidative processes. As fuel is metabolized via these oxidation processes, electrons will reduce molecular oxygen and provide energy needed for work. The end products of cellular respiration are carbon dioxide (CO2), water, and heat. So, it makes sense then that oxygen consumption, and CO2 expiration, are correlates of heat production. The easiest way to measure the heat produced by oxidative processes (metabolism) is through indirect calorimetry, which measures the rate of oxygen consumption. This rate correlates closely with metabolic activity in lean body mass. The most metabolically active tissues are the organs, which account for about 60% of basal oxygen consumption, whereas muscle mass accounts for only about 25%. Although these numbers seem modest, they far surpass the contribution of adipose tissue (2).

Metabolic Rate

Basal Metabolic Rate (BMR), or Basal Energy Expenditure (BEE), can be defined as the “measurement of oxygen consumed and carbon dioxide produced,” which can be thought of as the “energy expenditure necessary to support life”2. BMR is measured under controlled and standardized conditions, when the individual is postabsorptive (fasted), lying down, and completely at rest. This is usually an early morning measurement, performed upon wakening. It accounts for 50-70% of daily expenditure, whereas the resting energy expenditure (REE), which is a resting, but not a fasted, measure, accounts for 65-75% of daily total energy expenditure (2).

Although the BMR provides heat, under cold environmental conditions the process of shivering is activated. Shivering, or ‘involuntary muscle contraction’ provides 100% of the energy requirement of the heat needed to maintain core temperature3. Voluntary muscle contraction, like regular physical activity can account for up to 20-40% of the total daily expenditure, known as the thermic effect of activity (TEA; 2).

Diet-induced Thermogenesis (DIT)

The three main pieces of the metabolism pie are BMR, TEA, and the thermic effect of food (TEF), also known as diet-induced thermogenesis (DIT), and it represents the body’s processing of food, including “the digestion, absorption, transport, metabolism, and storage of energy from ingested food.” It contributes approximately 10-20% to the daily total energy expenditure (2).

Like exercise, or the TEA, DIT is variable in its contribution to the daily total energy expenditure. It has been shown that different foods from the same macronutrient category can yield different energy compositions, despite the fact that macronutrients are generally thought to yield a certain amount of kcals per gram. One example of this is dietary protein. A few studies that test the thermogenic responses to isoenergetic meals (meals having similar caloric compositions) agree that protein is the most thermogenic macronutrient (4,5,6,7,8,9). Not only is the thermal effect of protein larger than an isoenergetic meal of carbohydrate or fat, the type of proteins may vary in thermogenic responses. Casein protein may be one of the most thermogenic proteins since it is associated with greater body fat reductions (6) than other types, especially when combined with an exercise program (9).

The postprandial (post-meal) rise in energy expenditure with protein ingestion may be correlated with satiety, or the sensation of fullness (4,8). Although the mechanisms for this may be unclear, it has been thought that perhaps the increased rate in oxidative disposal of the excess protein and the formation of urea increase energy expenditure, which is sensed via thermoreceptors or the blood temperature by the hypothalamus. The hypothalamus, also involved in food intake regulation, then, activates the deceleration in hunger signals (4).

Thermogenesis – Obligatory versus facultative

The creation of heat and the maintenance of thermoregulation independent of the surrounding environment are unique to mammals. Thermogenic mechanisms are classified as either Obligatory or Facultative (or Adaptive). Obligatory thermogenesis (OT) is the energy released as heat during cellular and organ functions in the body, and the bulk of this heat is provided by the basal metabolic rate (10). Facultative thermogenesis (FT) is any additional heat produced in response to temperature, diet, or to cold exposure (11,12). To make things confusing, DIT has been considered partly obligatory (10) and facultative (4). Unlike OT, FT can be “switched on or off” and occurs mainly in skeletal muscle and brown adipose tissue (10). Sometimes the line between the two types of thermogenesis may begin to blurr!

Brown Adipose Tissue (BAT)

Brown adipose tissue (BAT) occurs in all newborn mammals, including humans. It is richly innervated with nerves and blood vessels, and is used as an organ for heat production, or non-shivering thermogenesis, in hibernating animals. As human infants’ thermoregulatory systems mature, BAT reduces. Unfortunately, our fat stores consist of the white/yellow adipocytes that have relatively few nerves and blood vessels. What makes BAT so unique is that this type of tissue is rich in mitochondria (double-membrane organelles, or the furnaces within a cell) and can increase heat production in response to the catecholamine, norepinephrine (NE; 3). The role of the sympathetic nervous system is critical for the heat production in BAT, and it has been shown that selective b3-receptor agonists stimulate BAT thermogenesis, as well as lipolysis in white adipose tissue (WAT; 13).

The thyroid gland also plays a significant role in the regulation of heat. It releases thyroxine to increase the metabolic rate of all cells in the body (3), and other thyroid hormones synergize with the sympathetic nervous system to regulate heat. Triiodothyronine (T3) facilitates the action of norepinephrine (NE) and also stimulates the expression of b-adrenergic receptors (b-AR). NE stimulates the activity of an enzyme (BAT Type II thyroxine 5’ deiodinase) in participation with the adrenergic receptor, a1-AR, to stimulate the response of uncoupling proteins (UCPs). Stimulation of UCPs through synergistic activity between NE (via cAMP) and T3 occurs at the gene level (13). Nobody panic, UCPs will be discussed later.

Sympathetic Nervous Activity and cAMP

When the brain senses cold, the sympathetic nerves are activated. NE release acts on the b-AR on the cell membrane of the brown adipocyte, which, in turn, activates a signal-transduction cascade, whereby cAMP activates Protein kinase A, mediating acute effects such as the stimulation of lipolysis and UCP-1 activity (UCP-1 is currently thought to be found only in BAT). Chronic effects include BAT hyperplasia, mitochondrial biogenesis, and UCP-1 gene transcription. The increase in free fatty acids liberated through b-adrenergic-stimulated lipolysis is thought to stimulate BAT UCP-1 activity (12).

These same effects do not occur in WAT or skeletal muscle. However, the sympathetic mediated cAMP cascade via b-AR does occur in these tissues, which increases the plasma concentrations of free fatty acids and glucose, through the activation of hormone sensitive lipase and glycogen phosphorylase, respectively. This effect is enhanced when phosphodiesterase is inhibited. This enzyme converts cAMP to the non-signalling molecule, 5’ – AMP. Methylxanthine derivatives, such as coffee, will inhibit phosphodiesterase, enhancing the signal molecule, cAMP, and the transduction cascade in the cell. Incidentally, b-agonists, such as sympathomimetics and thermogenic or weight loss aids function this same way. Many fat/weight loss aids include caffeine into their formula, in hopes of amplifying cAMP signaling by inhibiting the phosphodiesterase enzyme, to ensure greater fatty acid mobilization.

Uncoupling Proteins (Finally!)

Uncoupling proteins are thought to belong to a superfamily of proteins that may use mechanisms of protein import through complexes imbedded in the mitochondrial inner membrane (10). UCPs generate heat, rather than energy, due to uncoupled phosphorylation. I’ll explain.
As electron carriers, NADH and FADH2 donate the electrons to the electron transport chain (ETC), the electrons are shuttled through the inner membrane complexes (I-IV) where they are ultimately accepted by molecular oxygen. As the electrons pass complexes I, III, and IV, protons are pumped out into the intermembrane space where they create an acidic environment compared to the matrix, creating an electrochemical potential gradient. This proton gradient establishes a drive, or a proton motive force, which provides energy when the protons re-enter the mitochondrial matrix through the F0/F1-ATPase. That energy is used to synthesize ATP from shuttled-in cytosolic ADP. It has been proposed, however, if ADP is not available (in other words, cytosolic free energy of ATP is not falling and the cell is in a high-energy state), protons are unable to enter ATP-synthase. This denied entrance to the ATP pump creates “backpressure” on the proton pumps in the ETC, which inhibits further oxidation (12). To allow dissipation of this gradient and to defend against reactive oxygen species (ROS), another fate of the protons is the entrance into the mitochondrial matrix through a UCP (14). The energy is not used to synthesize ATP, but instead the energy in the protonmotive force is released as heat (12). This phenomenon is also known as mitochondrial proton “leak.” The requirements for this leak include oxygen consumption and a proton motive force, without the synthesis of ATP. In other words, it is the uncoupling between oxidation and phosphorylation (ATP synthesis). It has been suggested that the proton leak may account for up to 20% of the BMR (10).

UCP-1, found in BAT, is well characterized in terms of its regulation by adrenoreceptors and thyroid hormones (11,13); however, the mechanisms involved with its homologues, UCP-2 and UCP-3, are less clear. It has been suggested that proton transport by UCP-1 depends upon a histidine pair that may be absent in the other UCPs, resulting in a complete inability in proton transport by UCP-2, and only a partial ability for proton transport by UCP-3 (10). UCP-2 is expressed in a wide array of tissues, and is believed to be regulated by cAMP-dependent protein kinase. It is associated with a resistance to dietary-induced obesity due its role in being a negative regulator in b-cell insulin secretion (10).

UCP-3, on the other hand, is thought to be activated by both cAMP activation via b3-adrenergic stimulation, and thyroid hormone, and is expressed in rodent and human skeletal muscle. Since skeletal muscle is referred to as a thermogenic organ, UCP-3 has been considered to be involved in human energy metabolism. What has been discovered, is that UCP-3 expression is increased with high free-fatty acid concentrations, due to fasting, high-fat feeding, or exercise (10,14), suggesting its potential role in lipid metabolism. Interestingly, transgenic mice with over-expressed UCP-3 were hyperphagic, yet lean, had significant reductions in adipose tissue, and increased glucose clearance rates. One proposed mechanism for enhanced fatty acid oxidation may be that UCP-3 may act as a “mitochondrial fatty acid efflux protein” (10). This theory has also been proposed by Schrauwen and others (14) who suggest that since high intracellular levels of fatty acids can result in ROS formation, UCP-3 may play a role by allowing the fatty acid ions to translocate out of the matrix when their influx exceeds their oxidation, thereby preventing the fatty acids from lipid peroxidation.

Gene Transcription Factors and Gene Expression

UCPs may be regulated by transcription factors, and those that are commonly associated with thermogenesis are the Peroxisomal Proliferator Activated Receptors, or PPARs. These PPARs are named after peroxisomes, which are organelles similar to the mitochondrion, but they lack many of the inner mitochondrial membrane functions, like ATP resynthesis, due to its single membrane. Although these PPARs have several isoforms, including: a, b, d, g1, g2, the isoforms that are frequently mentioned in the context of thermogenesis are the PPARa and- g, and appear to be tissue-specific. PPARa is the dominant isoform in the liver and is involved in peroxisomal and mitochondrial b-oxidation of very long chain fatty acids, like those found in fish oil. Furthermore, PPARa is believed to be involved in the expression of UCP-2 and –3. Baillie15 and co-workers have shown that fish oil increases UCP-3 mRNA expression in skeletal muscle, as well as the expression of peroxisomal and mitochondrial enzymes involved in fat oxidation.

PPARg, on the other hand, is found in adipocytes and macrophages (16), and it has been suggested to increase UCP-2. Agonists of this activator, such as thiazolidinedione (TZD) drugs (used in the treatment for diabetes to lower insulin resistance), have been proposed to induce UCP-1 in vitro (10), and to cause hypertrophy of BAT in vivo (12). Together, PPARa and PPARg have been shown to be positive regulators of UCP-2 and UCP-3.

Studies done on UCP gene expression have verified that UCP-2 is abundantly expressed in WAT (17) and UCP-3 is abundantly expressed in skeletal muscle (15,17). Interestingly, mRNA expression for UCP-2 was significantly decreased in both heart and liver tissue with fish oil consumption (15). Without losing sight that UCPs represent “leak” and cellular “inefficiency,” it is intuitive, then, that uncoupled respiration in these tissues would be detrimental (17). Because research in this area is still very much unfamiliar territory, care must be taken when interpreting UCP data. On that note, when data suggests increases in UCP gene expression, this is not necessarily synonymous with increases in the protein! To illustrate the need for caution, 1993 data from Haddad et al. (18) shows that rats in spaceflight quickly double their mRNA expression for myosin heavy chain type IIb (fast-twitch, glycolytic muscle fibers) in response to unweighting in anti-gravity conditions. Although fast fiber protein expression increased, atrophy was the result.

Futile Cycles

Futile cycles are energetic reactions in which the net product is wasted energy, or ATP. Therefore, any of the ATP-ases (pumping processes that require energy) have the potential to lose efficiency. Examples of this include muscle relaxation during shivering, ion leaks, and substrate cycles. The contribution of the futile cycles to facultative (adaptive) thermogenesis is presently unknown, but it could be significant (12).

One of the most classic examples might be the substrate cycling involving the glycolytic/gluconeogenic pathways. The scenario involves the three enzymatic processes of glycolysis and the opposite gluconeogenic reactions that involve the stoichiometric difference of one ATP equivalent. In other words, if both glycolytic and gluconeogenic flux occurred simultaneously at the same rate, the net formal balance would be the hydrolysis of ATP.

The equation would look like this:

Fructose–6-phosphate + ATP --> fructose 1,6 bisphosphate + ADP
H2O + fructose 1,6 bisphosphate --> fructose-6-phosphate + Pi
-------------------------------------------------------
The Net: H2O + ATP --> ADP + Pi

Apparently, the only useful part of this process was the hydrolysis of ATP, or “wasted energy.”

Although hormonal and other mechanisms play a role to control the flux and the rate at which this type of futile substrate cycling occurs in vivo, this type of cycling can drain the ATP pool, warranting the increases in carbon source consumption, oxygen consumption, and respiratory rates (19).

Another very interesting form of substrate cycling may involve the hormone, leptin. Leptin, known for its ability to regulate adipose stores of triacylglycerol, may increase energy expenditure in a couple of ways. It is thought to stimulate the hypothalamic-pituitary-thyroid axis to produce more T3, which can stimulate UCPs, thereby increasing mitochondrial proton leak, and/or leptin, itself, may increase UCP mRNA expression. But more importantly, leptin administration has been shown to play a role in triacylglycerol/fatty acid (TAG/FA) cycling in which fatty acids undergo lipolysis and immediate reesterification, at the expense of 8 mol of ATP/cycle of reesterification. This type of cycling occurs primarily for the sake of dissipating energy for thermogenesis and weight reduction, and interestingly, its activity is low in the obese. Along with the induction of TAG/FA cycling, Reidy and Weber (20) have discovered leptin is capable of activating lipolysis, fatty acid oxidation, and shifting the fuel preference from carbohydrates to lipids.

Knowing JB, he is well aware of this thermogenic effect of leptin and could be in a room somewhere concocting a way to bottle this hormone!

The hormone insulin, if in circulation in the plasma along with free fatty acids, may begin to promote the process of triglyceride (TG) reesterification. Therefore, thermogenic aids designed for weight loss, which are recommended to be taken before a meal, may stimulate sympathomimetic-induced lipolysis, mobilizing free fatty acids into circulation. Upon insulin release with food ingestion, these circulating fatty acids would then be reesterified, taking advantage of the futile cycling and the energy cost associated with it. In effect, “burning energy while you eat.” However, I imagine this effect would not last long, since the increase in insulin concentrations would stimulate the phosphodiesterase enzyme, thereby quenching the cAMP cascade signaling pathway that stimulates lipolysis through hormone sensitive lipase. Therefore, many of these thermogenic agents mobilize and oxidize more fuel when used during exercise. However, because they mimic the sympathetic nervous response they can be potentially dangerous.

If I haven’t lost you during the PPARs and the UCPs, this might do it:

Similar futile cycles have been shown to occur with ions. In the case of calcium cycling in rabbit skeletal muscle, the amount of heat released during the hydrolysis of each ATP molecule depends on whether there is “leak” in the sarcoplasmic reticular vesicle membrane (21,22) and the energy state of the cell (22). Exothermic reactions in which Ca2+ transport has uncoupled ATP activity is when vesicles are “leaky” due to a low ADP/ATP ratio (high energy state of the cell) and a lack of gradient across the membrane. However, in situations with a high ADP/ATP ratio (dropping/low energy state of the cell), the vesicles and gradient are intact, and the energy that is released is absorbed. In this case, the Ca2+ transport is endothermic and ATPase uncoupling does not occur (22).

A classic example of the calcium ion cycling occurs in the ‘heater organs’ of billfish. This specialized tissue lacks contractile protein, but is abundant in mitochondria, acetylcholine receptors, sarcoplasmic reticulum (SR), and T-tubules. Depolarization-initiated SR releases Ca2+ and then it is returned again to the SR by ATP consumption by the Ca-ATPase. This futile cycling occurs for the sole purpose of heat generation for the brain and eyes of the fish during cold water dives (12).

The leak from human skeletal muscle Sodium/Potassium (Na+/K+) ATPase–pump may also make a significant contribution to the body’s ‘wasted’ energy. The Na+/K+ pump works efficiently at pumping three Na+ molecules out of the cells and two K+ back in to the cell with the cost of one mol of ATP. During muscular activity, the K+ that is pumped out of the cell due to depolarization should be transported back in via Na+/K+ ATPase; however, much of this K+ is lost to the interstitial space where it equilibrates with plasma. Perhaps as the free energy of ATP falls (falling energy state of the cell), the pump gets “sloppy,” and never recaptures the correct stoichiometric amount of K+ back into the cells. As a result, the leakage of K+ during exercise may amount to ~3 times what can be taken up by the Na/K pumps, and once again, energy is wasted (23).

A mechanism that may reduce the increased plasma concentrations of K+ during exercise also requires energy. Lindinger and coworkers (24) have shown, by using human red blood cells (RBCs) and post exercise human plasma ex vivo, that RBCs actively take up the plasma K+ (~67%) by Na+/K+ pumping. This means, that if the researchers have duplicated what actually occurs in vivo, then during exercise, it may take twice the amount of ATP for K+ molecules to find their way back into the cell.

Conclusion

Adaptive or facultative thermogenesis involves the additive processes that occur independently of basal processes necessary to sustain life. However, some of these obligatory thermogenic processes can be modulated, induced, and increased, thereby changing their contributions to energy expenditure. Sympathomimetic agents taken to imitate the action of catecholamines can increase substrate availability in muscle and white adipose, and thyroid hormone action. Protein increases energy expenditure, and omega –3 fatty acids increase gene and expression and thermogenesis via increases in mitochondrial uncoupling and fat oxidation enzymes. Substrate and ion cycling may account for much of the ATP/energy loss in the cells, requiring more consumption of substrate and oxygen, and increased respiration to compensate for these inefficiencies. Apparently, the contribution that adaptive thermogenesis makes to energy expenditure may be more significant than originally thought. It seems as though the body is full of physiologically imperfect systems, it makes one wonder, are these imperfections our perceived flaws of wasted energy, or are they deliberate, clever, and necessary mechanisms critical for survival?

About the Author

Tammy Thomas is a registered dietitian, a certified strength and conditioning specialist (CSCS), and has earned a Master's degree in Exercise Science focusing on Nutritional and Exercise Biochemistry. Currently she does training and nutrition writing and consulting for individuals with rheumatoid arthritis and other autoimmune diseases. She can be reached at tammy@proactivitysupport.com.

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