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Thermogenesis is the process of heat production in organisms. It occurs in all warm-blooded animals, and also in a few species of thermogenic plants such as the Eastern skunk cabbage, the Voodoo lily ( Sauromatum venosum ), and the giant water lilies of the genus Victoria . The lodgepole pine dwarf mistletoe, Arceuthobium americanum , disperses its seeds explosively through thermogenesis. [1]
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:
One method to raise temperature is through shivering. It produces heat because the conversion of the chemical energy of ATP into kinetic energy causes almost all of the energy to show up as heat. 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.
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Non-shivering thermogenesis occurs in brown adipose tissue (brown fat) [3] that is present in almost all eutherians (swine being the only exception currently known [4] [5] ). [6] 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 (H+), thus enabling mitochondria to burn fatty acids and oxygen to generate heat. [7] 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. [8] [9] UCP1 is locked in a cytoplasmic-open state by guanosine triphosphate in a pH-dependent manner, preventing proton leak. [10]
In this process, substances such as free fatty acids (derived from triacylglycerols) remove purine (ADP, GDP and others) inhibition of thermogenin, which causes an influx of H+ 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 Ca2+ pump. [11] Thermogenesis is contributed to by futile cycles, such as the simultaneous occurrence of lipogenesis and lipolysis [12] or glycolysis and gluconeogenesis. In a broader context, futile cycles can be influenced by activity/rest cycles such as the Summermatter cycle. [13]
Acetylcholine stimulates muscle to raise metabolic rate. [14]
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 [15] and is available in CITGeneDB. [16]
The biological processes which allow for thermogenesis in animals did not evolve from a singular, common ancestor. [17] Rather, avian (birds) and eutherian (placental mammalian) lineages developed the ability to perform thermogenesis independently through separate evolutionary processes. [17] The fact that the same evolutionary character evolved independently in two different lineages after their last known common ancestor means that thermogenic processes are classified as an example of convergent evolution. However, while both clades are capable of performing thermogenesis, the biological processes involved are different. The reason that avians and eutherians both developed the capacity to perform thermogenesis is a subject of ongoing study by evolutionary biologists, and two competing explanations have been proposed to explain why this character appears in both lineages. [17]
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. [18] 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. [19] 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. [19] 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. [17] 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. [18] 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. [19] [17] [18]
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). [20] 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. [21] 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. [21]
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. [17] In skeletal muscle NST, Calcium ions slip across muscle cells to generate heat. [17] Even though BAT NST was originally thought to be the only process by which animals could maintain endothermy, scientists now suspect that skeletal muscle NST was the original form of the process and that BAT NST developed later. [17] Though scientists once also believed that only birds maintained their body temperatures using skeletal muscle NST, research in the late 2010s showed that mammals and other eutherians also use this process when they do not have adequate stores of brown adipose tissue in their bodies. [22]
Skeletal muscle NST might also be used to maintain body temperature in heterothermic mammals during states of torpor or hibernation. [17] Given that early eutherians and the reptiles which later evolved into avian lineages were either heterothermic or ectothermic, both forms of NST are thought not to have developed fully until after the K-pg extinction roughly 66 million years ago. [23] However, some estimates place the evolution of these characters earlier, at roughly 100 mya. [24] 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.
Non-shivering thermogenesis is regulated mainly by thyroid hormone and the sympathetic nervous system. Some hormones, such as norepinephrine and leptin, may stimulate thermogenesis by activating the sympathetic nervous system. Rising insulin levels after eating may be responsible for diet-induced thermogenesis (thermic effect of food). Progesterone also increases body temperature.
Warm-blooded is an informal term referring to animal species whose bodies maintain a temperature higher than that of their environment. In particular, homeothermic species maintain a stable body temperature by regulating metabolic processes. Other species have various degrees of thermoregulation.
Brown adipose tissue (BAT) or brown fat makes up the adipose organ together with white adipose tissue. Brown adipose tissue is found in almost all mammals.
An endotherm is an organism that maintains its body at a metabolically favorable temperature, largely by the use of heat released by its internal bodily functions instead of relying almost purely on ambient heat. Such internally generated heat is mainly an incidental product of the animal's routine metabolism, but under conditions of excessive cold or low activity an endotherm might apply special mechanisms adapted specifically to heat production. Examples include special-function muscular exertion such as shivering, and uncoupled oxidative metabolism, such as within brown adipose tissue.
Adipose tissue is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and a variety of immune cells such as adipose tissue macrophages. Its main role is to store energy in the form of lipids, although it also cushions and insulates the body.
Thermogenin is a mitochondrial carrier protein found in brown adipose tissue (BAT). It is used to generate heat by non-shivering thermogenesis, and makes a quantitatively important contribution to countering heat loss in babies which would otherwise occur due to their high surface area-volume ratio.
SERCA, or sarcoplasmic/endoplasmic reticulum Ca2+-ATPase, or SR Ca2+-ATPase, is a calcium ATPase-type P-ATPase. Its major function is to transport calcium from the cytosol into the sarcoplasmic reticulum.
Thermogenic plants have the ability to raise their temperature above that of the surrounding air. Heat is generated in the mitochondria, as a secondary process of cellular respiration called thermogenesis. Alternative oxidase and uncoupling proteins similar to those found in mammals enable the process, which is still poorly understood.
An uncoupling protein (UCP) is a mitochondrial inner membrane protein that is a regulated proton channel or transporter. An uncoupling protein is thus capable of dissipating the proton gradient generated by NADH-powered pumping of protons from the mitochondrial matrix to the mitochondrial intermembrane space. The energy lost in dissipating the proton gradient via UCPs is not used to do biochemical work. Instead, heat is generated. This is what links UCP to thermogenesis. However, not every type of UCPs are related to thermogenesis. Although UCP2 and UCP3 are closely related to UCP1, UCP2 and UCP3 do not affect thermoregulatory abilities of vertebrates. UCPs are positioned in the same membrane as the ATP synthase, which is also a proton channel. The two proteins thus work in parallel with one generating heat and the other generating ATP from ADP and inorganic phosphate, the last step in oxidative phosphorylation. Mitochondria respiration is coupled to ATP synthesis, but is regulated by UCPs. UCPs belong to the mitochondrial carrier (SLC25) family.
Mitochondrial uncoupling protein 2 is a protein that in humans is encoded by the UCP2 gene.
Mitochondrial uncoupling protein 3 is a protein that in humans is encoded by the UCP3 gene. The gene is located in chromosome (11q13.4) with an exon count of 7 and is expressed on the inner mitochondrial membrane. Uncoupling proteins transfer anions from the inner mitochondrial membrane to the outer mitochondrial membrane, thereby separating oxidative phosphorylation from synthesis of ATP, and dissipating energy stored in the mitochondrial membrane potential as heat. Uncoupling proteins also reduce generation of reactive oxygen species.
G-protein coupled receptor 3 is a protein that in humans is encoded by the GPR3 gene. The protein encoded by this gene is a member of the G protein-coupled receptor family of transmembrane receptors and is involved in signal transduction.
PR domain containing 16, also known as PRDM16, is a protein which in humans is encoded by the PRDM16 gene.
Sarcolipin is a micropeptide protein that in humans is encoded by the SLN gene.
Brain mitochondrial carrier protein 1 is a protein that in humans is encoded by the SLC25A14 gene.
A eurytherm is an organism, often an endotherm, that can function at a wide range of ambient temperatures. To be considered a eurytherm, all stages of an organism's life cycle must be considered, including juvenile and larval stages. These wide ranges of tolerable temperatures are directly derived from the tolerance of a given eurythermal organism's proteins. Extreme examples of eurytherms include Tardigrades (Tardigrada), the desert pupfish, and green crabs, however, nearly all mammals, including humans, are considered eurytherms. Eurythermy can be an evolutionary advantage: adaptations to cold temperatures, called cold-eurythemy, are seen as essential for the survival of species during ice ages. In addition, the ability to survive in a wide range of temperatures increases a species' ability to inhabit other areas, an advantage for natural selection.
A myokine is one of several hundred cytokines or other small proteins and proteoglycan peptides that are produced and released by skeletal muscle cells in response to muscular contractions. They have autocrine, paracrine and/or endocrine effects; their systemic effects occur at picomolar concentrations.
Daniel Ricquier, is a French biochemist known for his work in mitochondria and hereditary metabolic diseases. Ricquier has been a member of the French Academy of Sciences since 2002, and a professor of biochemistry and Molecular Biology at the Faculty of Medicine of the University of Paris Descartes since 2003.
Antonio Vidal-Puig is a Spanish medical doctor and scientist who works as a Professor of Molecular Nutrition and Metabolism at the University of Cambridge (UK), best known for advancing the concept that pharmacological targeting of brown fat may serve to treat overweight and obesity in affected individuals, as well as for introducing the concept of adipose tissue "expandability" as an important factor in the pathogenesis of insulin resistance in the context of positive energy balance. His published work focuses on areas such as adipose tissue metabolism and lipotoxicity, regulation of insulin secretion, and the pathophysiology of metabolic syndrome, obesity, and type 2 diabetes. In April 2024, he was granted the rank of doctor honoris causa from the King Juan Carlos University, Madrid.
Barbara Cannon is a British-Swedish biochemist, physiologist and an academic. She is an emeritus professor at Stockholm University as well as the chairman of the scientific advisory board at The Helmholtz Centre. She is also a consultant at Combigene.
Jan Nedergaard is a physiologist, academic, and researcher. He is Professor of Physiology at the Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University.