Thermogenesis

Types

Depending on whether or not they are initiated through locomotion and intentional movement of the muscles, thermogenic processes can be classified as one of the following:

• Obligatory thermogenesis: Heat generated from energy expenditure for vital metabolic processes necessary to sustain an organism at rest. Obligatory thermogenesis includes both cellular work (e.g., active transport, cell division, DNA replication) and organ work (e.g., myocardial contractility, liver detoxification, renal filitration).
• Exercise activity thermogenesis (EAT)
• Non-exercise activity thermogenesis (NEAT): Energy expended for any spontaneous physical activity that is not a structured exercise routine or sports-like exercise. This can include but is not limited to walking, leisure activities, fidgeting, and maintaining posture.
• Diet-induced thermogenesis (DIT): Energy expended to process the nutrients in food.

Shivering

One method animals use to raise temperature is through shivering. When an animal shivers, almost all the energy being expended shows up as heat. While shivering does not produce useful motion, it is still valuable for raising an animal's body temperature. For example, shivering is the process by which the body temperature of hibernating mammals (such as some bats and ground squirrels) is raised as these animals emerge from hibernation.

Non-shivering

Non-shivering thermogenesis occurs in brown adipose tissue (brown fat) that is present in almost all eutherians (swine being the only exception currently known). Brown adipose tissue has a unique uncoupling protein (thermogenin, also known as uncoupling protein 1) that allows for the synthesis of ATP to be uncoupled from the production of protons (), thus enabling mitochondria to burn fatty acids and oxygen to generate heat. The atomic structure of human uncoupling protein 1 UCP1 has been solved by cryogenic-electron microscopy. The structure has the typical fold of a member of the SLC25 family. UCP1 is locked in a cytoplasmic-open state by guanosine triphosphate in a pH-dependent manner, preventing proton leak.

High levels of free fatty acids within cells play a pivotal role in regulating mitochondrial uncoupling by stimulating proton leak. The stimulation of beta oxidation by increased levels of hormones such as thyroid hormone or noreinephrine helps to activate non-shivering thermogenesis during cold exposure. In this process, free fatty acids (derived from triacylglycerols) remove purine (ADP, GDP and others) inhibition of thermogenin, which causes an influx of into the matrix of the mitochondrion and bypasses the ATP synthase channel. This uncouples oxidative phosphorylation, and the energy from the proton motive force is dissipated as heat rather than producing ATP from ADP, which would store chemical energy for the body's use. Thermogenesis can also be produced by leakage of the sodium-potassium pump and the pump. Thermogenesis is contributed to by futile cycles, such as the simultaneous occurrence of lipogenesis and lipolysis or glycolysis and gluconeogenesis. In a broader context, futile cycles can be influenced by activity/rest cycles such as the Summermatter cycle.

Acetylcholine stimulates muscle to raise metabolic rate.

The low demands of thermogenesis mean that free fatty acids draw, for the most part, on lipolysis as the method of energy production.

A comprehensive list of human and mouse genes regulating cold-induced thermogenesis (CIT) in living animals (in vivo) or tissue samples (ex vivo) has been assembled and is available in CITGeneDB.

Evolutionary history

In avians and eutherians

The biological processes which allow for thermogenesis in animals did not evolve from a singular, common ancestor.

One explanation for the convergence is the "aerobic capacity" model. This theory suggests that natural selection favored individuals with higher resting metabolic rates, and that as the metabolic capacity of birds and eutherians increased, they developed the capacity for endothermic thermogenesis. Researchers have linked high levels of oxygen consumption with high resting metabolic rates, suggesting that the two are directly correlated. Rather than animals developing the capacity to maintain high and stable body temperatures only to be able to thermoregulate without the aid of the environment, this theory suggests that thermogenesis is actually a by-product of natural selection for higher aerobic and metabolic capacities. These higher metabolic capacities may initially have evolved for the simple reason that animals capable of metabolizing more oxygen for longer periods of time would have been better suited to, for example, run from predators or gather food. This model explaining the development of thermogenesis is older and more widely accepted among evolutionary biologists who study thermogenesis.

The second explanation is the "parental care" model. This theory proposes that the convergent evolution of thermogenesis in birds and eutherians is based on shared behavioral traits. Specifically, birds and eutherians both provide high levels of parental care to young offspring. This high level of care is theorized to give new born or hatched animals the opportunity to mature more rapidly because they have to expend less energy to satisfy their food, shelter, and temperature needs. The "parental care" model thus proposes that higher aerobic capacity was selected for in parents as a means of meeting the needs of their offspring. While the "parental care" model does differ from the "aerobic capacity" model, it shares some similarities in that both explanations for the rise of thermogenesis rest on natural selection favoring individuals with higher aerobic capacities for one reason or another. The primary difference between the two theories is that the "parental care" model proposes that a specific biological function (childcare) resulted in selective pressure for higher metabolic rates.

Despite both relying on similar explanations for the process by which organisms gained the capacity to perform non-shivering thermogenesis, neither of these explanations has secured a large enough consensus to be considered completely authoritative on convergent evolution of NST in birds and mammals, and scientists continue to conduct studies which support both positions.

Non-shivering thermogenesis

Brown Adipose Tissue (BAT) thermogenesis is one of the two known forms of non-shivering thermogenesis (NST). This type of heat-generation occurs only in eutherians, not in birds or other thermogenic organisms. BAT NST occurs when Uncoupling Protein 1 (UCP1) performs oxidative phosphorylation in eutherians' bodies resulting in the generation of heat (Berg et al., 2006, p. 1178). This process generally only begins in eutherians after they have been subjected to low temperatures for an extended period of time, after which the process allows an organism's body to maintain a high and stable temperature without a reliance on environmental thermoregulation mechanisms (such as sunlight/shade). Because eutherians are the only clade which store brown adipose tissue, scientists previously thought that UCP1 evolved in conjunction with brown adipose tissue. However, recent studies have shown that UCP1 can also be found in non-eutherians like fish, birds, and reptiles. This discovery means that UCP1 probably existed in a common ancestor before the radiation of the eutherian lineage. Since this evolutionary split, though, UCP1 has evolved independently in eutherians, through a process which scientists believe was not driven by natural selection, but rather by neutral processes like genetic drift.

Evolution of Skeletal-Muscle Non-Shivering Thermogenesis

The second form of NST occurs in skeletal muscle. While eutherians use both BAT and skeletal muscle NST for thermogenesis, birds only use the latter form. This process has also been shown to occur in rare instances in fish.

Skeletal muscle NST might also be used to maintain body temperature in heterothermic mammals during states of torpor or hibernation. However, some estimates place the evolution of these characters earlier, at roughly 100 mya. It is most likely that the process of evolving the capacity for thermogenesis as it currently exists was a process which began prior to the K-pg extinction and ended well after. The fact that skeletal muscle NST is common among eutherians during periods of torpor and hibernation further supports the theory that this form of thermogenesis is older than BAT NST. This is because early eutherians would not have had the capacity for non-shivering thermogenesis as it currently exists, so they more frequently used torpor and hibernation as means of thermal regulation, relying on systems which, in theory, predate BAT NST. However, there remains no consensus among evolutionary biologists on the order in which the two processes evolved, nor an exact timeframe for their evolution.

Regulation

Non-shivering thermogenesis is regulated mainly by the synergistic effect of thyroid hormone (TH) and the sympathetic nervous system (SNS) on brown adipose tissue. When BAT is stimulated by norepinephrine released by the SNS, this triggers an intracellular cascade which increases the conversion of the less active thyroxine (T4) to the more active triiodothyronine (T3) within the tissue. T3 then increases the expression of UCP1 in BAT, enhancing heat production. TH also increases obligatory thermogenesis through stimulating metabolism, energy production and utilization. Other sources of heat production stimulated by TH include the sodium-potassium pump, and calcium ion cycling in muscle. Rising insulin levels after eating may be responsible for diet-induced thermogenesis (thermic effect of food) through increased glucose uptake. Intranasal insulin has been shown to increase metabolic rate by inhibiting warm-sensitive hypothalamic neurons, whose role is to lower body temperature in response to perceived warmth. Inhibiting these neurons stimulates BAT thermogenesis. Progesterone also increases body temperature.

While commonly thought to directly stimulate BAT thermogenesis, the mechanism by which leptin increases thermogenesis is through inhibiting torpor, which raises the body temperature threshold where heat-conserving mechanisms such as vasoconstriction will start to occur. Leptin deficient mice perceive a deficit in energy, triggering the body to conserve energy by reducing metabolic rate (torpor), which also lowers the body temperature threshold.

Thermogenic Compounds as a Treatment for Obesity

There are several pharmaceuticals that can stimulate different types of thermogenesis, with varying levels of safety. Caffeine, for example, has been shown to increase both resting metabolic rate and energy expenditure from exercise, thus enhancing obligatory thermogenesis as well as exercise-induced thermogenesis. Caffeine has also been used in combination with Ephedrine, a sympathomimetic, and aspirin, a mitochondrial uncoupler, to promote weight loss and has shown some clinical efficacy. Ephedrine, due to increased risk of side effects such as hypertension, tachycardia, and stroke contributing to increased risk of death or permanent disability, was banned by the FDA in 2004. Caffeine is generally considered to be safe at doses up to 400 mg/day, with increased risk of cardiac events and seizures with increasing dose.

2,4-Dinitrophenol (DNP) is another uncoupler, which is much more potent than aspirin, and also more toxic, with a risk of triggering hyperthermia, tachycardia, and tachypnea which eventually is fatal. The chemical uncoupling of oxidative phosphorylation by DNP causes low ATP in cells by allowing protons to leak through the mitochondrial membrane instead of being used in ATP synthase, which leads to loss of energy as heat, triggering rapid catabolism of fats and carbohydrates (and thus weight loss) to replenish ATP levels, which further amplifies heat production. It has historically been used as a weight loss agent but is still widely available, mainly through online pharmacies, despite being banned for human consumption in 1938 due its toxicity.

Thermogenesis from white adipose tissue

A novel and interesting method named the thermogenin-like system (TLS) has recently been proposed to produce thermogenesis from white adipose tissue or from other substantial tissues (such as endothelial or muscle cells). Ultimately, this could lead to new therapeutic methods for treating morbid obesity or severe diabetes. The proposed model is purely theoretical and relies on the use of light-activated PoXeR pumps integrated into the inner membrane of mitochondria. These pumps allow the passage of protons in such a way that the proton motive force is reduced. This would enable greater consumption of blood glucose from white adipose, endothelial, or muscle cells, thereby potentially lowering blood glucose levels. The explanation is that glycolysis is accelerated when glucose enters the cells and undergoes the Krebs cycle in the mitochondria. Since muscle cells have many mitochondria, it is also interesting to express PoXeR pumps in this tissue.

However, the method is invasive, relies on gene therapy, and requires several clinical trials as well as hospitalization to integrate the system at the level of white or muscle adipose tissue in the abdominal fat. It is also a light-responsive system. Since light does not penetrate the skin from the outside, the system must include an under-skin component with alternating activation of green light for a certain duration, followed by deactivation for another period. This cycle repeats over several weeks, particularly to recharge the light system. To ensure that ATP levels do not drop too low (otherwise the cell dies), the system self-regulates. Indeed, for light to be activated in the system, it is necessary to have a mechanism that continuously provides light without significantly lowering ATP levels. As luciferase can emit light in exchange for ATP, if ATP levels decrease too drastically, the light stops, ATP levels rise again, and the light is reactivated to induce thermogenesis.

Independently, Glen Jeffery and Michael B. Powner studied in 2024 the impact of light on mitochondria in order to reduce blood glucose levels. This work is quite similar to that of Daoudi Rédoane.

References

References

1. (February 2015). "Thermogenesis-triggered seed dispersal in dwarf mistletoe". Nature Communications.
2. (2018). "Effect of Iodothyronines on Thermogenesis: Focus on Brown Adipose Tissue". Front Endocrinol (Lausanne).
3. (2022). "((Endotext [Internet]))". MDText.com.
4. (2011). "Human Physiology". McGraw Hill.
5. (August 2006). "The uncoupling protein 1 gene (UCP1) is disrupted in the pig lineage: a genetic explanation for poor thermoregulation in piglets". PLOS Genetics.
6. (April 2017). "Pig Has No Brown Adipose Tissue". The FASEB Journal.
7. (1992). "Evolution of brown fat: its absence in marsupials and monotremes". Canadian Journal of Zoology.
8. (January 2004). "Brown adipose tissue: function and physiological significance". Physiological Reviews.
9. (March 2020). "The SLC25 Mitochondrial Carrier Family: Structure and Mechanism". Trends in Biochemical Sciences.
10. (September 2020). "The SLC25 Carrier Family: Important Transport Proteins in Mitochondrial Physiology and Pathology". Physiology.
11. (June 2023). "Structural basis of purine nucleotide inhibition of human uncoupling protein 1". Science Advances.
12. (March 2003). "Characterization of ryanodine receptor and Ca2+-ATPase isoforms in the thermogenic heater organ of blue marlin (Makaira nigricans)". The Journal of Experimental Biology.
13. (November 2004). "The direct effect of leptin on skeletal muscle thermogenesis is mediated by substrate cycling between de novo lipogenesis and lipid oxidation". FEBS Letters.
14. (November 2012). "PGC-1α and exercise in the control of body weight". International Journal of Obesity.
15. (June 2015). "Fever and the thermal regulation of immunity: the immune system feels the heat". Nature Reviews. Immunology.
16. (January 2018). "CITGeneDB: a comprehensive database of human and mouse genes enhancing or suppressing cold-induced thermogenesis validated by perturbation experiments in mice". Database.
17. (2017-11-09). "Muscle Non-shivering Thermogenesis and Its Role in the Evolution of Endothermy". Frontiers in Physiology.
18. (March 2000). "Energy assimilation, parental care and the evolution of endothermy". Proceedings. Biological Sciences.
19. (November 1979). "Endothermy and activity in vertebrates". Science.
20. (August 2006). "The uncoupling protein 1 gene (UCP1) is disrupted in the pig lineage: a genetic explanation for poor thermoregulation in piglets". PLOS Genetics.
21. (January 2009). "Molecular evolution of UCP1 and the evolutionary history of mammalian non-shivering thermogenesis". BMC Evolutionary Biology.
22. (August 2016). "Increased Reliance on Muscle-based Thermogenesis upon Acute Minimization of Brown Adipose Tissue Function". The Journal of Biological Chemistry.
23. (2019). "Encyclopedia of Ecology". Elsevier.
24. (February 2021). "Thyroid hormones in the regulation of brown adipose tissue thermogenesis". Endocr Connect.
25. (December 1995). "Thyroid hormone control of thermogenesis and energy balance". Thyroid.
26. (June 1986). "Insulin. Its role in the thermic effect of glucose". J Clin Invest.
27. (September 2016). "Warm-Sensitive Neurons that Control Body Temperature". Cell.
28. (January 2011). "Intranasal insulin enhances postprandial thermogenesis and lowers postprandial serum insulin levels in healthy men". Diabetes.
29. (April 2020). "Leptin: Is It Thermogenic?". Endocr Rev.
30. (January 1989). "Normal caffeine consumption: influence on thermogenesis and daily energy expenditure in lean and postobese human volunteers". The American Journal of Clinical Nutrition.
31. (May 2019). "Caffeine enhances activity thermogenesis and energy expenditure in rats". Clinical and Experimental Pharmacology and Physiology.
32. (1985-05-01). "Contribution of BAT and skeletal muscle to thermogenesis induced by ephedrine in man". American Journal of Physiology. Endocrinology and Metabolism.
33. (2004-01-01). "Salicylic Acid Is an Uncoupler and Inhibitor of Mitochondrial Electron Transport". Plant Physiology.
34. (February 1993). "Ephedrine, caffeine and aspirin: safety and efficacy for treatment of human obesity". International Journal of Obesity and Related Metabolic Disorders: Journal of the International Association for the Study of Obesity.
35. (2000-12-21). "Adverse Cardiovascular and Central Nervous System Events Associated with Dietary Supplements Containing Ephedra Alkaloids". New England Journal of Medicine.
36. Program, Human Foods. (2024-10-01). "Small Entity Compliance Guide: Final Rule Declaring Dietary Supplements Containing Ephedrine Alkaloids Adulterated Because They Present an Unreasonable Risk".
37. (2024-05-29). "Caffeine". StatPearls Publishing.
38. (September 2011). "2,4-Dinitrophenol (DNP): A Weight Loss Agent with Significant Acute Toxicity and Risk of Death". Journal of Medical Toxicology.
39. (April 2020). "Diet aid or aid to die: an update on 2,4-dinitrophenol (2,4-DNP) use as a weight-loss product". Archives of Toxicology.
40. Daoudi, Redoane. (2018). "Can the light be used to treat obesity and diabetes?".
41. (17 May 2024). "Light stimulation of mitochondria reduces blood glucose levels". Journal of Biophotonics.