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Understanding non-shivering thermogenesis

Understanding non-shivering thermogenesis

Search ADS. Physiol Genom — In Understanding non-shivering thermogenesis review, Understanding non-shivering thermogenesis summarize the anatomical and thermogwnesis differences between rodent and human BAT, current useful and mostly non-invasive methods in studying human BAT, as well as recent advancements targeting thermogenic adipocytes as a means to combat metabolic diseases in humans. Understanding non-shivering thermogenesis

Understanding non-shivering thermogenesis -

body temperatures]. This line may be extrapolated stippled line to zero. Thus, when the difference between the ambient and body temperatures is zero, heat loss is zero. This is therefore the controlled defended temperature i.

the body temperature. Curves such as those shown in Fig. It may therefore be questioned whether the animals under normal conditions experimentally, this simply means in their home cages increase their metabolism to the same extent.

This can be deduced from food intake, because animals must replenish all of the energy that is lost as heat. Thus, at 5°C, a mouse will have a food intake approximately 3—4 times that at 30°C. Although the thermoneutral zone is operationally defined as the temperature zone at which the lowest metabolic rate is observed, a nominal value for a given species cannot be tabulated.

Normally, the thermoneutral zone for mice is said to be 29—31°C Fig. However, for newborn and young animals, the zone moves to higher temperatures, approaching body temperature. By contrast, gestational and lactating mammals produce vast amounts of heat due to foetal metabolism and as a by-product of milk production Roberts and Coward, ; Quek and Trayhurn, This means that the thermoneutral zone moves markedly down the temperature scale, perhaps to approximately 15°C, in lactating mice.

It also follows that any genetic manipulation may alter the thermoneutral zone, notably due to manipulation-induced alterations in insulation as will be discussed below.

Thus, nominal temperatures that are thermoneutral for wild-type mice may not be so for manipulated mice. Consequently, mice of the two genotypes may have to be placed at different nominal temperatures to obtain an identical functional temperature — conditions that will probably not be readily accepted by most reviewers but that are in reality the correct way to perform the experiments.

Thus, the thermoneutral zone should optimally be established in independent studies for any mouse modification before further experiments are undertaken. Although this seems a harsh demand, reality has demonstrated that it may be well worth the effort. In extension of this, the fact that mice are very small — compared with rats — may qualitatively affect the outcome of metabolic experiments.

Because of their size, rats are not as cold sensitive as mice. Adult rats probably have a lower critical temperature that approaches 24°C and it may even be slightly lower under normal housing conditions.

This means that, under normal housing conditions, adult male rats may be experiencing thermoneutrality whereas this is never the case for mice. Apparent physiological differences between rats and mice may therefore be due to the rats being studied under thermoneutral conditions whereas the mice are cold-stressed, leading to qualitatively different outcomes.

Similarly, differences between younger and older rats — or between female and male rats — may be secondary to their different thermoneutral zones rather than being true manifestations of age or sexual dimorphisms.

Considering the significance of the thermal responses for metabolic studies, it is remarkable that differences in thermal responses are very poorly documented with regard to age, sex, strains, etc. Even within humans, females are generally smaller than males and thus probably have a different thermoneutral zone.

Clearly, they have zones of comfort some degree higher than those of men Rohles, Thus, again, metabolic differences between men and women, examined under conditions with identical nominal temperatures, may in reality be secondary to differences in thermal responses rather than to more basic metabolic modalities.

All mammals exposed to cold will initially shiver in order to elevate heat production Griggio, Thus, extensive periods of life in the cold would seem difficult and stressful.

However, during the Second World War, cold-room food stores were invaded with mice that apparently lived there all their life, even had their young there and seemed to thrive well under conditions that would seem very unpleasant for all small mammals —10°C Barnett, That all of this would happen under conditions of constant shivering seemed unlikely.

The effect of increased insulation on the thermoneutral zone. As seen, animals with a better insulation a smaller slope of the line must necessarily also obtain a broader thermoneutral zone, because the line must extrapolate to the same defended body temperature.

What was unexpectedly observed in rodents in the s was that after a prolonged period in the cold, the animals ceased to shiver but retained an equally high metabolic rate Sellers et al.

This would allow for a more comfortable life in the cold. As this elevated metabolism was observed to occur in the absence of measurable shivering, it was appropriately termed nonshivering thermogenesis. The mediator and site of this nonshivering thermogenesis were initially unknown.

Starting from experiments originally directed at thyroid hormone effects Ring, , it turned out that the disappearance of shivering was accompanied by an increase in the thermogenic response to adrenergic stimulation, i. the mediator was norepinephrine noradrenaline , released from the sympathetic nervous system Hsieh and Carlson, ; Depocas, Consequently, it was concluded that it was possible to estimate the capacity for nonshivering thermogenesis in an animal by injecting norepinephrine into the animal when it was at its thermoneutral temperature.

Although this technique indeed activates nonshivering thermogenesis by mimicking the release of norepinephrine from specific regions of the sympathetic nervous system, it also unavoidably activates other adrenergic receptors in the body. This leads to some elevation of metabolism and thus to an overestimate of the nonshivering thermogenic capacity, as will be discussed below.

The organ generating nonshivering thermogenesis remained controversial long after the mediator was identified. Many researchers believed that the predominant site was skeletal muscle, mainly because of its large size and thus potential large capacity for heat production.

Based on now classical studies by R. Smith in the s Smith, ; Smith and Hock, ; Cameron and Smith, ; Smith, ; Smith and Roberts, , a few scientists believed that brown adipose tissue was the main site of nonshivering thermogenesis.

That brown adipose tissue could generate heat was not in question, but the magnitude and thus significance of the heat production were controversial, particularly considering the small size of the organ.

The controversy was resolved by the blood flow studies of Foster and colleagues in the late s, which demonstrated massive blood flow increases to brown adipose tissue, both on cold exposure Foster and Frydman, and following norepinephrine injection Foster and Frydman, , with no increases in blood flow to skeletal muscle; the blood leaving brown adipose tissue was also observed to be practically depleted in oxygen.

Since then, practically all rodent researchers have agreed that brown adipose tissue is — at least — the main site of nonshivering thermogenesis; some, such as we, would maintain that it is the only site. Concerning humans, the idea that nonshivering thermogenesis provided it exists originates from muscle has persisted, not least because it has been the general view that brown adipose tissue did not exist in adults.

Very recent observations have altered this view reviewed in Nedergaard et al. We would consider it likely that, in humans too, all nonshivering thermogenesis emanates from brown adipose tissue.

During the s and onwards, studies were also performed that showed that brown adipose tissue went through a process of cell proliferation and increased differentiation when an animal was kept in a cold environment Cameron and Smith, Hence, the growth of the tissue could be seen both as the reason and the rate-limiting step for the development of nonshivering thermogenesis.

This growth of brown adipose tissue following prolonged cold exposure is termed recruitment. In addition to the increased cell proliferation Hunt and Hunt, ; Bukowiecki et al. The basic principles for heat production in brown adipose tissue.

The brown-fat cells are stimulated by norepinephrine NE released from the sympathetic nervous system. The norepinephrine binds, as indicated, to its receptor in the plasma membrane, and through intracellular signalling processes, this leads to degradation of the triglycerides TG in the lipid droplets, and the released free fatty acids FFA interact with uncoupling protein-1 UCP1 and, through this, overcome the inhibition of UCP1 caused by cytosolic purine nucleotides such as ATP and ADP, GTP and GDP.

This leads to respiration in the mitochondria that is uncoupled from ATP synthesis. All energy from the combustion of substrate food is therefore directly released as heat. Thus, classical nonshivering thermogenesis is a facultative meaning that it can be turned on and off within minutes , adaptive meaning that it needs weeks to develop form of thermogenesis that can be acutely induced by norepinephrine injection i.

an adrenergic thermogenesis. In the s, the biochemical mechanism for heat production in brown adipose tissue was extensively investigated. It became apparent that the heat production occurred in the mitochondria as a consequence of a regulated uncoupling process mediated by a unique protein Nicholls, The protein was isolated in Lin and Klingenberg, and is now known as UCP1.

In Fig. In resting cells, the activity of UCP1 is inhibited by bound purine nucleotides. When the cell is activated by norepinephrine, a lipolytic cascade is initiated that results in UCP1 activation.

The exact mechanism of this activation is still not fully resolved Nedergaard et al. During early mammalian evolution, UCP1 developed rapidly Saito et al.

UCP1 is principally found in all mammals — with the pig family being the only exception Berg et al. Pigs have secondarily lost the ability to express UCP1 and are thus incapable of nonshivering thermogenesis Mount, In our opinion, UCP1 is the only true thermogenic uncoupling protein, and the other proteins with similar names UCP2—5 have received their names based on homology in amino acid sequence, not on homology in function.

To delineate the significance of brown adipose tissue under different physiological conditions, animals without brown adipose tissue would really be necessary.

However, such animals have been difficult to generate, either by attempts to dissect away brown fat which cannot be done adequately as the tissue depots are found in so many places or by molecular means. However, because of the significance of UCP1 for the thermogenic mechanism of brown adipose tissue, a mouse with a genetic ablation of UCP1 Enerbäck et al.

Therefore, with such a mouse as an experimental tool, many questions concerning the significance of brown adipose tissue heat production under different physiological conditions have now been stringently addressed.

As anticipated, brown adipocytes isolated from UCP1-ablated mice do not respond to norepinephrine addition with an increase in oxygen consumption, i. they do not show adrenergic thermogenesis Matthias et al.

However, the basal respiration of the cells is identical regardless of whether they possess UCP1. it does not allow for proton flux over the mitochondrial membrane when it is not directly stimulated. UCP1-ablated mice are viable and fertile.

In agreement with the results from the isolated brown adipocytes, there are no differences in basal metabolic rate between mice with and without UCP1 Golozoubova et al.

This confirms the tenet that UCP1 is not leaky and does not contribute to basal metabolic rate. The UCP1-ablated mice were initially observed to be unable to defend body temperature when transferred from normal animal house temperatures of approximately 23 to 5°C Enerbäck et al. Although at first sight, this appears to be the expected result if brown adipose tissue were to be ascribed a major role in nonshivering thermogenesis, it seems to be in contradiction to the tenet that mammals initially shiver to maintain body temperature.

However, the outcome is understandable within this tenet. A mouse with an ablation in the UCP1 gene that has been living at normal animal house temperatures will have been unable to develop any capacity for thermogenesis in its brown adipose tissue because of the lack of UCP1.

Its survival at 23°C has been dependent on the constant use of shivering to increase metabolism. If such an animal is transferred to 5°C, it will — unlike the wild-type animal — have no brown adipose tissue activity, and is therefore forced to rely entirely upon shivering to defend its body temperature.

The capacity and endurance of the shivering prove to be inadequate, and gradually the body temperature of the UCP1-ablated animal therefore decreases.

If a UCP1-ablated mouse is housed at an intermediate, cooler temperature, such as 18°C, it can then be transferred to 5°C and survive for prolonged periods Golozoubova et al.

Similarly, if the ambient temperature is successively decreased 2°C day —1 , the UCP1-ablated mice survive in the cold Ukropec et al. It seemed initially possible that such cold-acclimated mice had developed an alternative means of nonshivering thermogenesis.

However, measurements of electrical activity in muscle i. shivering showed that, in contrast to the case in wild-type mice, these UCP1-ablated mice shiver with the same intensity after several weeks in the cold as they do on the initiation of exposure to cold Golozoubova et al.

They have thus not developed any alternative nonshivering thermogenesis. Simple visual inspection of the mice in the cold also makes it clear that whereas the cold-acclimated wild-type mice are comfortable in the cold and move around normally, principally similarly to behaviour at normal temperatures, the cold-acclimated UCP1-ablated mice remain in one position, in the nest if possible, curled up and visibly shivering.

Thus, there is no evidence that an alternative mechanism for nonshivering thermogenesis has developed. Rather it would seem that the endurance capacity of the mouse for shivering has increased, and its muscles therefore do not become exhausted, which allows for the uninterrupted maintenance of shivering and, therefore, defence of body temperature.

Alterations in muscle capacity are indeed observable in cold-acclimated UCP1-ablated mice, measurable as alterations in muscle mitochondria ATP-synthase capacity Shabalina et al. Thus, no other adaptive adrenergic mechanism of thermogenesis exists or is induced in these mice.

We would therefore maintain that all classical nonshivering thermogenesis is located in brown adipose tissue. Until recently, it has been the general contention that there must be an alternative mechanism for heat production in muscle because it was believed that so-called thyroid hormone thermogenesis took place in muscle.

However, it now seems likely that even thyroid hormone thermogenesis emanates from brown adipose tissue, due to thyroid hormone stimulation of the areas in the brain that control brown adipose tissue activity Sjögren et al.

The metabolism of mice is often examined using a cold tolerance test. The mice may be able to cope with this challenge, or they may immediately or successively succumb to the cold Fig.

This test indeed tests the cold tolerance of the mice, but does not examine nonshivering thermogenesis capacity, despite many implications of this in the literature. Typical results of a cold tolerance test. The animals may either be able to defend their body temperature indefinitely a or they may immediately b or after some time c succumb to the cold.

In an acute situation such as this, the extra heat needed comes mainly from shivering, so this experiment mainly tests shivering endurance; however, factors such as animal insulation, heart and lung performance and delivery of substrate e.

fatty acids from the white adipose tissue to the muscle may also be limiting for the cold tolerance. Therefore, this test does not explicitly examine the capacity for adaptive nonshivering thermogenesis, a process that takes weeks in the cold to develop.

What it really tests is dependent on the previous thermal history of the animal, which determines the contribution of brown fat thermogenesis to total thermogenesis, and on the ability of an animal to elevate and maintain its total metabolism at the level needed to survive at the exposure temperature, through shivering.

Regardless of whether an animal has brown adipose tissue, it must nonetheless elevate its total metabolism to the same extent in order to defend its body temperature. There are statements in the literature that imply that warming an animal through shivering thermogenesis should in some way be more energetically costly than heating it by nonshivering thermogenesis.

This suggestion is difficult to reconcile with thermodynamics, and we are unaware of any experimental demonstration of this phenomenon. Indeed the metabolic rates of mice that produce their heat through shivering or nonshivering thermogenesis are identical Golozoubova et al.

In a cold tolerance experiment, a fraction of the metabolic increase may be from brown fat and the remainder from shivering, or it may all derive from shivering. If the animal fails to maintain body temperature, it can be for any of a variety of reasons.

The failure could indeed indicate an inadequacy in brown fat, but equally well an inadequacy in the ability to maintain shivering i. that there is a muscle problem , or that the heart or lungs are unable to meet the challenge of such a high elevation of metabolic rate.

A further confounding issue with such a test, if it is used to investigate the significance of a particular gene in genetically modified mice, is that the gene of interest may alter the insulation of the mouse. As shown in Fig.

If the gene of interest has actually made the fur more sparse, the mouse will, in practice, be exposed to a greater cold challenge and may cool more quickly than the wild-type mice. This could have been interpreted to mean that the gene of interest impairs brown fat thermogenesis but, as will be understood, this is clearly an inadequate interpretation.

The outcome of a cold tolerance test is much influenced by the thermal prehistory of the mice. We can compare two such prehistories. If a wild-type mouse is first maintained at its thermoneutral temperature, approximately 30°C, and is then acutely transferred to 5°C, it will have to increase its metabolism immediately three- to fourfold see Fig.

Some time later its body temperature and thus its metabolism may decrease Fig. Thus, the cold challenge is too great for the mouse to cope with: its ability to maintain a level of shivering that can counteract the cold for a prolonged period is insufficient. This can be interpreted in the way that at thermoneutral temperatures, the animal develops little or no brown adipose tissue.

Consequently, on exposure to temperatures below thermoneutral, it will be entirely dependent on shivering thermogenesis for heat production. Constant shivering requires muscles with a capacity for constant endurance activity. Should this endurance ability fail, the animal has no other means to defend body temperature and its body temperature will decrease principally as illustrated in Fig.

However Fig. normal animal house temperatures, for a prolonged period, it will recruit brown adipose tissue and UCP1 to the extent required to compensate for the temperature challenge represented by these temperatures.

When such an animal is transferred to 5°C, it will keep full activity in its brown adipose tissue. However, this capacity will be insufficient, as it is adequate only for 23°C. Therefore, the animal will also shiver at a level necessary to compensate for the remainder of the cold demand Jansky et al.

It thus has available the limited brown adipose tissue capacity plus its total shivering capacity. This means that it only needs to use a fraction of its shivering capacity and does not overtax this system.

It can therefore cope with this sudden cold challenge. This illustrates one ecological advantage of developing brown fat thermogenic capacity: the ability to be prepared for successively decreasing temperatures.

Effect of thermal prehistory on shivering demand. Animals pre-exposed to temperatures below thermoneutrality will develop a capacity for nonshivering thermogenesis NST adequate for that temperature. When the animals are acutely exposed to 4°C, the demand for shivering to compensate for the rest of the heat loss at 4°C is therefore reduced.

Such animals will therefore manage better in a cold tolerance test Fig. Theoretical figure based on the data shown in Fig. Because it is norepinephrine that activates nonshivering thermogenesis, one means to evaluate the nonshivering thermogenic capacity of an animal is to treat it acutely with norepinephrine to mimic activation of the sympathetic nervous system Fig.

Depending on the previous history of the animal, the magnitude of the response will vary. Under physiological circumstances, when an animal is exposed to cold, it will attempt to activate whatever brown fat it possesses.

This is mediated by activation of the sympathetic nerves that directly innervate the brown adipose tissue depots Foster et al. This is thus not a generalized sympathetic activation but a highly localized one Cannon and Nedergaard, However, when norepinephrine is injected into an animal, a concentration must be given that is sufficiently high to mimic the local synaptic concentration Depocas et al.

This results in all the cells of the animal being bathed in a high amount of norepinephrine. As essentially all cells possess adrenergic receptors that are coupled to metabolic responses of some type, an elevation of metabolism will ensue that is independent of brown fat and that does not occur under physiological circumstances.

This response can therefore be seen as a purely pharmacological response and does not demonstrate any adaptive responsiveness. It leads to an overestimation of nonshivering thermogenic capacity because its magnitude can only be accurately evaluated in mice with a genetic ablation of UCP1.

The magnitude of the adrenergic response in animals that have been housed at their thermoneutral temperature is a fairly close approximation Fig. Effect of cold acclimation on the thermogenic response to norepinephrine NE.

NE was injected into wild-type mice which can produce heat in their brown adipose tissue and into UCP1-ablated mice UCP1 KO which are unable to do this ; the mice were acclimated to 30 or 4°C for at least 1 mo. There was no effect of the presence or absence of UCP1 with regard to the basal metabolic rate before norepinephrine injection.

Acclimation to cold led to some increase in basal respiration probably related to the effects of the several-times larger food intake in these mice. Cold acclimation had no effect on the response to NE in the UCP1 KO mice. Only in the mice that possess UCP1 does acclimation to cold result in an increased response to NE.

It corresponds to the development of adaptive nonshivering thermogenesis, and the increase due to cold acclimation represents the recruitment of brown adipose tissue i. the mice get more brown-fat cells, with more mitochondria and more UCP1 [V.

Golozoubova, B. and J. Golozoubova et al. In animals with an extremely high capacity for nonshivering thermogenesis and with a good insulation, such a high heat production may be induced by norepinephrine that the animal becomes hyperthermic, as it cannot dissipate heat, and then this type of experiment cannot be undertaken.

Nonshivering thermogenic capacity can be determined in awake, non-anaesthetized animals Jansky et al. Principally, an acute stress response is induced by the injection itself, in addition to the direct norepinephrine-induced thermogenesis.

To improve the reproducibility of the measurements and decrease the number of animals required, anaesthetized animals can be studied. It is not possible to use inhalation anaesthetics as these inhibit brown fat activity Ohlson et al. The term endothermy is often taken to imply a pattern of homeothermic endothermy, i.

However, many endothermic mammals and birds are actually abandoning homeothermy during challenging periods and undergo heterothermic phases during which they reduce T b and metabolic rate in a state of torpor Ruf and Geiser, Up to date at least species of heterothermic mammals and birds have been identified Ruf and Geiser, and it is now widely accepted that heterothermy is a plesiomorphic, ancient trait from which homeothermy has evolved Grigg et al.

The mammalian ancestor was likely a small, nocturnal insectivorous animal that regularly used torpor Luo et al. In placental heterotherms UCP1 plays an important role during rewarming from torpor Nedergaard and Cannon, A study on UCP1-ablated mice has shown that although the lack of UCP1-mediated NST does not impair the expression of a full torpor bout i.

However, the mice were kept at warm conditions prior to the experiment, which prevents the cold-induced increase of muscle NST reported in later studies Bal et al. Therefore, animals likely had to primarily rely on shivering thermogenesis and were not able to use muscle NST for rewarming.

It would be interesting to see if cold acclimatization of animals prior to the experiment would lead to a differing result. Nevertheless, these data suggest that uncoupling of the proton gradient in BAT might have evolved to allow for a more rapid arousal and reduced energetic costs for rewarming, because slow rewarming increases the time spent at high metabolic rates Oelkrug et al.

If UCP1-ablated mice have lower rewarming rates this should also be the case for monotremes and marsupials. Unfortunately, there is no comprehensive comparison between rewarming rates of marsupiala and placentalia that also take into account differences in T a and T b.

Among known heterothermic mammals, i. These subzero T b s are known from at least eight species Ruf and Geiser, , e. Low tissue temperatures pose a problem because of Arrhenius effects, i. These Arrhenius effects may hamper, or at least significantly slow down, rewarming to euthermia.

Theoretically, this problem could be overcome by local heating of a small thermogenic tissue, i. This is one of the properties of BAT and therefore BAT is likely not only increasing the speed of arousals from torpor, but was also important for rewarming from torpor at low T b s. Even if the temperatures at earth were warmer at the time of BAT evolution, animals will still have experienced daily and yearly fluctuations, similar to daily fluctuations in tropical habitats seen today.

Not surprisingly then, the local heating of BAT can be even detected by thermal imaging of skin e. Arguably then, the evolution of BAT was especially beneficial for heterothermic placental mammals, as it allowed them to tolerate lower levels of T b as a result of the enormous reduction of metabolic rate during hibernation and torpor Ruf and Geiser, This likely enhanced adaptive radiation of placental mammals and their ability to overwinter in the north-temperate and arctic zones.

These are climates that are significantly colder than those inhabited by marsupials and monotremes, among which a preference for warm habitats ranging from rainforests to deserts is an ancestral trait Mitchell et al. If the evolution of BAT indeed facilitated the use of hibernation, the lack of BAT in birds may help to explain why there is only a single bird species known to truly hibernate Jaeger, ; Woods and Brigham, , although a number of birds show shallow daily torpor Ruf and Geiser, This suggests that the bird thermoregulatory phenotype, compared with the typical small mammal, is characterized by a high degree of homeothermy, little heterothermy, and high exercise performance.

Given their lack of BAT, it seems surprising then that muscle NST, or a combination of muscle NST and shivering, is sufficient to allow many birds to maintain very high 42°C T b even during cold exposure. In cold-acclimated ducklings skeletal-muscles were identified as the major site of NST Duchamp and Barre, The fact that muscle NST seems more efficient in birds might be partially related to the better insulation of feathers in comparison with mammalian hair Aschoff, While birds can decrease their conductance enormously during cold exposure due the air trapped in the rigid feather structure, mammalian hair is softer and less suitable to trap air as an insulation barrier McNab, However, we suggest that there is another main reason for a lack of selective advantages of a BAT-like tissue in birds, which—to our knowledge—has never been considered before: skeletal muscles in birds already reach metabolic rates that are at least twice as high as in exercising small mammals, and can be as high as 8—18 times BMR Butler et al.

The rate-limiting step causing this difference between mammals and birds is the much greater capacity of avian skeletal muscles to take up circulating fatty acids reviewed in Jenni-Eiermann, It seems logical then that placental mammals, possessing BAT, would much benefit from enhanced fatty acid import, compared with skeletal muscle cells.

This is indeed ensured by the function of lipoprotein lipase, which, along with other enzymes, allows the massive import of fatty acids into BAT during thermogenesis at significantly higher rates than into skeletal muscle cells of placental mammals Heldmaier et al.

Interestingly, when the capacity of fatty acid import into muscle cells was increased by overexpression of lipoprotein lipase in transgenic mice, this improved cold resistance—independent from BAT thermogenesis—and elevated muscular fatty acid oxidation Jensen et al.

As noted by Jensen et al. Arguably, these differences in fuel import capacity into thermogenic tissues may well-explain the absence of BAT in birds, as well as the lower thermogenic capacity of marsupials and monotremes. In summary, it seems that muscle NST may have been an important step in the evolution of endothermy.

Endothermy is clearly facilitated by increasing mitochondrial membrane surface Else and Hulbert, and activity of the sodium-potassium pump, which is the greatest contributor to BMR Clarke et al.

However, apart from shivering, muscle NST via SERCA ATP hydrolysis was probably the first metabolic pathway in mammals solely used for thermogenesis.

Interestingly, after mixed support for this model from smaller studies over the last decades, strong evidence for the aerobic capacity model comes from a recent comprehensive phylogenetically informed study ranging from fish and amphibians to birds and mammals, which shows that there is in fact a positive correlation between maximum and resting metabolic rates in mammals, and that this pattern is a result of natural selection Nespolo et al.

These findings again point to an important role of enhanced muscle function and metabolism for the emergence of endothermy. One of the reasons why the importance of muscle NST may have been underestimated in the past but see, e. In contrast, activation of UCP1-mediated NST occurs prior to the onset of shivering Böckler and Heldmaier, which makes it easier to identify as a separate mechanism.

However, even NST in BAT can also occur simultaneously with shivering thermogenesis Böckler and Heldmaier, Arguably then, the evolution of endothermy was not characterized by switches from one to another, possibly improved, metabolic pathway. Instead it seems that increasing levels of endothermy were achieved by recruiting additional mechanisms of thermogenesis to muscular work during locomotion, including specialized shivering thermogenesis, increases in mitochondrial density and membrane leakage, increases in sodium-potassium pump activity, shifts in SERCA activity toward NST.

Highly endothermic mammals living in cold environments apparently can use all of these mechanisms simultaneously. There are several possible selective advantages to this last evolutionary step, the additional recruitment of UCP1-mediated NST.

As already pointed out previously Rowland et al. Further, we suggest that the evolution of BAT in addition to muscle NST was related to heterothermy being predominant among early endothermic mammals. This is because, in comparison with large muscles, a small dedicated thermogenic tissue such as BAT is much more suited to rapidly warm up and escape limiting Arrhenius effects of low tissue temperature during hibernation and torpor in harsh habitats.

Finally, we argue that additional mechanisms for NST are not required by animals that have enhanced capacities to fuel muscle NST by high rates of fatty acid import. Such a group of endotherms are birds, which probably evolved this superior fuel transport capacity as an adaptation to flight. This would explain why birds have high endothermic capacities, despite the absence of BAT.

JN wrote the first draft of the manuscript. All authors added text, discussed, and edited the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Seasonal changes in the critical arousal temperature of the marsupial Sminthopsis crassicaudata correlate with the thermal transition in mitochondrial respiration.

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PLOS ONE 8:e In certain hibernators another stimulus, photoperiod, promotes growth or regression of brown adipose tissue. The neural regulation of thermogenesis in brown adipose tissue is thus not only part of the central control mechanisms involved in thermoregulation but also part of those involved in the regulation of energy balance.

In hibernators , such as the hamster, the neural regulation of thermogenesis in brown adipose tissue includes, in addition, central components that control the function of brown adipose tissue during entry into and arousal from hibernation and pineal or melatonin-related components that control its growth in response to photoperiod.

In animals which become intermittently torpid, such as the mouse, the regulation includes in addition central components that control the function of brown adipose tissue during entry into and arousal from torpor.

Nonshivering Understanding non-shivering thermogenesis was originally defined as thermogebesis cold-induced increase in heat Metabolic health community not associated with the muscle activity non-shiverkng Pre-workout snacks. Recent research shows it Pre-workout snacks thermogehesis a thsrmogenesis process located primarily in brown Dark chocolate revolution tissue and controlled by the Pre-workout snacks of the sympathetic nervous supply of this tissue. Another stimulus to sympathetic nervous activity, the ingestion of food, promotes diet-induced thermogenesis in brown adipose tissue. Brown adipose tissue grows and regresses in accordance with the extent to which it is stimulated, either by cold or by diet, and the capacity of the animal for cold-induced nonshivering thermogenesis and diet-induced thermogenesis increases or decreases accordingly. In certain hibernators another stimulus, photoperiod, promotes growth or regression of brown adipose tissue. Undestanding thermogenic mechanisms supporting endothermy are still not Pre-workout snacks understood Non-shiverung all major mammalian subgroups. In non-shiveging mammals, brown adipose Carbohydrate loading and recovery drinks currently represents the most accepted source Non-sihvering adaptive Understanding non-shivering thermogenesis thermogenesis. Non-shvering mitochondrial protein UCP1 uncoupling protein 1 catalyzes heat production, but the conservation of this mechanism is unclear in non-placental mammals and lost in some placentals. Here, we review the evidence for and against adaptive non-shivering thermogenesis in marsupials, which diverged from placentals about — million years ago. We critically discuss potential mechanisms that may be involved in the heat-generating process among marsupials.

Understanding non-shivering thermogenesis -

With the growing interest in the potential therapeutic benefits of shivering and nonshivering skeletal muscle to counter the effects of neuromuscular, cardiovascular, and metabolic diseases, we expect this field to continue its growth in the coming years.

Keywords: SERCA; electromyography; energy metabolism; excitation-contraction coupling; nonshivering thermogenesis; proton leak; shivering; skeletal muscle. Abstract Humans have inherited complex neural circuits which drive behavioral, somatic, and autonomic thermoregulatory responses to defend their body temperature.

Publication types Review. The exact mechanism of this activation is still not fully resolved Nedergaard et al. During early mammalian evolution, UCP1 developed rapidly Saito et al. UCP1 is principally found in all mammals — with the pig family being the only exception Berg et al.

Pigs have secondarily lost the ability to express UCP1 and are thus incapable of nonshivering thermogenesis Mount, In our opinion, UCP1 is the only true thermogenic uncoupling protein, and the other proteins with similar names UCP2—5 have received their names based on homology in amino acid sequence, not on homology in function.

To delineate the significance of brown adipose tissue under different physiological conditions, animals without brown adipose tissue would really be necessary.

However, such animals have been difficult to generate, either by attempts to dissect away brown fat which cannot be done adequately as the tissue depots are found in so many places or by molecular means. However, because of the significance of UCP1 for the thermogenic mechanism of brown adipose tissue, a mouse with a genetic ablation of UCP1 Enerbäck et al.

Therefore, with such a mouse as an experimental tool, many questions concerning the significance of brown adipose tissue heat production under different physiological conditions have now been stringently addressed.

As anticipated, brown adipocytes isolated from UCP1-ablated mice do not respond to norepinephrine addition with an increase in oxygen consumption, i. they do not show adrenergic thermogenesis Matthias et al. However, the basal respiration of the cells is identical regardless of whether they possess UCP1.

it does not allow for proton flux over the mitochondrial membrane when it is not directly stimulated. UCP1-ablated mice are viable and fertile. In agreement with the results from the isolated brown adipocytes, there are no differences in basal metabolic rate between mice with and without UCP1 Golozoubova et al.

This confirms the tenet that UCP1 is not leaky and does not contribute to basal metabolic rate. The UCP1-ablated mice were initially observed to be unable to defend body temperature when transferred from normal animal house temperatures of approximately 23 to 5°C Enerbäck et al. Although at first sight, this appears to be the expected result if brown adipose tissue were to be ascribed a major role in nonshivering thermogenesis, it seems to be in contradiction to the tenet that mammals initially shiver to maintain body temperature.

However, the outcome is understandable within this tenet. A mouse with an ablation in the UCP1 gene that has been living at normal animal house temperatures will have been unable to develop any capacity for thermogenesis in its brown adipose tissue because of the lack of UCP1.

Its survival at 23°C has been dependent on the constant use of shivering to increase metabolism. If such an animal is transferred to 5°C, it will — unlike the wild-type animal — have no brown adipose tissue activity, and is therefore forced to rely entirely upon shivering to defend its body temperature.

The capacity and endurance of the shivering prove to be inadequate, and gradually the body temperature of the UCP1-ablated animal therefore decreases. If a UCP1-ablated mouse is housed at an intermediate, cooler temperature, such as 18°C, it can then be transferred to 5°C and survive for prolonged periods Golozoubova et al.

Similarly, if the ambient temperature is successively decreased 2°C day —1 , the UCP1-ablated mice survive in the cold Ukropec et al. It seemed initially possible that such cold-acclimated mice had developed an alternative means of nonshivering thermogenesis.

However, measurements of electrical activity in muscle i. shivering showed that, in contrast to the case in wild-type mice, these UCP1-ablated mice shiver with the same intensity after several weeks in the cold as they do on the initiation of exposure to cold Golozoubova et al.

They have thus not developed any alternative nonshivering thermogenesis. Simple visual inspection of the mice in the cold also makes it clear that whereas the cold-acclimated wild-type mice are comfortable in the cold and move around normally, principally similarly to behaviour at normal temperatures, the cold-acclimated UCP1-ablated mice remain in one position, in the nest if possible, curled up and visibly shivering.

Thus, there is no evidence that an alternative mechanism for nonshivering thermogenesis has developed. Rather it would seem that the endurance capacity of the mouse for shivering has increased, and its muscles therefore do not become exhausted, which allows for the uninterrupted maintenance of shivering and, therefore, defence of body temperature.

Alterations in muscle capacity are indeed observable in cold-acclimated UCP1-ablated mice, measurable as alterations in muscle mitochondria ATP-synthase capacity Shabalina et al.

Thus, no other adaptive adrenergic mechanism of thermogenesis exists or is induced in these mice. We would therefore maintain that all classical nonshivering thermogenesis is located in brown adipose tissue.

Until recently, it has been the general contention that there must be an alternative mechanism for heat production in muscle because it was believed that so-called thyroid hormone thermogenesis took place in muscle.

However, it now seems likely that even thyroid hormone thermogenesis emanates from brown adipose tissue, due to thyroid hormone stimulation of the areas in the brain that control brown adipose tissue activity Sjögren et al. The metabolism of mice is often examined using a cold tolerance test.

The mice may be able to cope with this challenge, or they may immediately or successively succumb to the cold Fig. This test indeed tests the cold tolerance of the mice, but does not examine nonshivering thermogenesis capacity, despite many implications of this in the literature.

Typical results of a cold tolerance test. The animals may either be able to defend their body temperature indefinitely a or they may immediately b or after some time c succumb to the cold. In an acute situation such as this, the extra heat needed comes mainly from shivering, so this experiment mainly tests shivering endurance; however, factors such as animal insulation, heart and lung performance and delivery of substrate e.

fatty acids from the white adipose tissue to the muscle may also be limiting for the cold tolerance. Therefore, this test does not explicitly examine the capacity for adaptive nonshivering thermogenesis, a process that takes weeks in the cold to develop.

What it really tests is dependent on the previous thermal history of the animal, which determines the contribution of brown fat thermogenesis to total thermogenesis, and on the ability of an animal to elevate and maintain its total metabolism at the level needed to survive at the exposure temperature, through shivering.

Regardless of whether an animal has brown adipose tissue, it must nonetheless elevate its total metabolism to the same extent in order to defend its body temperature.

There are statements in the literature that imply that warming an animal through shivering thermogenesis should in some way be more energetically costly than heating it by nonshivering thermogenesis.

This suggestion is difficult to reconcile with thermodynamics, and we are unaware of any experimental demonstration of this phenomenon. Indeed the metabolic rates of mice that produce their heat through shivering or nonshivering thermogenesis are identical Golozoubova et al. In a cold tolerance experiment, a fraction of the metabolic increase may be from brown fat and the remainder from shivering, or it may all derive from shivering.

If the animal fails to maintain body temperature, it can be for any of a variety of reasons. The failure could indeed indicate an inadequacy in brown fat, but equally well an inadequacy in the ability to maintain shivering i. that there is a muscle problem , or that the heart or lungs are unable to meet the challenge of such a high elevation of metabolic rate.

A further confounding issue with such a test, if it is used to investigate the significance of a particular gene in genetically modified mice, is that the gene of interest may alter the insulation of the mouse. As shown in Fig. If the gene of interest has actually made the fur more sparse, the mouse will, in practice, be exposed to a greater cold challenge and may cool more quickly than the wild-type mice.

This could have been interpreted to mean that the gene of interest impairs brown fat thermogenesis but, as will be understood, this is clearly an inadequate interpretation. The outcome of a cold tolerance test is much influenced by the thermal prehistory of the mice.

We can compare two such prehistories. If a wild-type mouse is first maintained at its thermoneutral temperature, approximately 30°C, and is then acutely transferred to 5°C, it will have to increase its metabolism immediately three- to fourfold see Fig.

Some time later its body temperature and thus its metabolism may decrease Fig. Thus, the cold challenge is too great for the mouse to cope with: its ability to maintain a level of shivering that can counteract the cold for a prolonged period is insufficient.

This can be interpreted in the way that at thermoneutral temperatures, the animal develops little or no brown adipose tissue. Consequently, on exposure to temperatures below thermoneutral, it will be entirely dependent on shivering thermogenesis for heat production.

Constant shivering requires muscles with a capacity for constant endurance activity. Should this endurance ability fail, the animal has no other means to defend body temperature and its body temperature will decrease principally as illustrated in Fig.

However Fig. normal animal house temperatures, for a prolonged period, it will recruit brown adipose tissue and UCP1 to the extent required to compensate for the temperature challenge represented by these temperatures.

When such an animal is transferred to 5°C, it will keep full activity in its brown adipose tissue. However, this capacity will be insufficient, as it is adequate only for 23°C.

Therefore, the animal will also shiver at a level necessary to compensate for the remainder of the cold demand Jansky et al. It thus has available the limited brown adipose tissue capacity plus its total shivering capacity. This means that it only needs to use a fraction of its shivering capacity and does not overtax this system.

It can therefore cope with this sudden cold challenge. This illustrates one ecological advantage of developing brown fat thermogenic capacity: the ability to be prepared for successively decreasing temperatures. Effect of thermal prehistory on shivering demand.

Animals pre-exposed to temperatures below thermoneutrality will develop a capacity for nonshivering thermogenesis NST adequate for that temperature. When the animals are acutely exposed to 4°C, the demand for shivering to compensate for the rest of the heat loss at 4°C is therefore reduced.

Such animals will therefore manage better in a cold tolerance test Fig. Theoretical figure based on the data shown in Fig. Because it is norepinephrine that activates nonshivering thermogenesis, one means to evaluate the nonshivering thermogenic capacity of an animal is to treat it acutely with norepinephrine to mimic activation of the sympathetic nervous system Fig.

Depending on the previous history of the animal, the magnitude of the response will vary. Under physiological circumstances, when an animal is exposed to cold, it will attempt to activate whatever brown fat it possesses.

This is mediated by activation of the sympathetic nerves that directly innervate the brown adipose tissue depots Foster et al. This is thus not a generalized sympathetic activation but a highly localized one Cannon and Nedergaard, However, when norepinephrine is injected into an animal, a concentration must be given that is sufficiently high to mimic the local synaptic concentration Depocas et al.

This results in all the cells of the animal being bathed in a high amount of norepinephrine. As essentially all cells possess adrenergic receptors that are coupled to metabolic responses of some type, an elevation of metabolism will ensue that is independent of brown fat and that does not occur under physiological circumstances.

This response can therefore be seen as a purely pharmacological response and does not demonstrate any adaptive responsiveness.

It leads to an overestimation of nonshivering thermogenic capacity because its magnitude can only be accurately evaluated in mice with a genetic ablation of UCP1. The magnitude of the adrenergic response in animals that have been housed at their thermoneutral temperature is a fairly close approximation Fig.

Effect of cold acclimation on the thermogenic response to norepinephrine NE. NE was injected into wild-type mice which can produce heat in their brown adipose tissue and into UCP1-ablated mice UCP1 KO which are unable to do this ; the mice were acclimated to 30 or 4°C for at least 1 mo.

There was no effect of the presence or absence of UCP1 with regard to the basal metabolic rate before norepinephrine injection. Acclimation to cold led to some increase in basal respiration probably related to the effects of the several-times larger food intake in these mice.

Cold acclimation had no effect on the response to NE in the UCP1 KO mice. Only in the mice that possess UCP1 does acclimation to cold result in an increased response to NE. It corresponds to the development of adaptive nonshivering thermogenesis, and the increase due to cold acclimation represents the recruitment of brown adipose tissue i.

the mice get more brown-fat cells, with more mitochondria and more UCP1 [V. Golozoubova, B. and J. Golozoubova et al. In animals with an extremely high capacity for nonshivering thermogenesis and with a good insulation, such a high heat production may be induced by norepinephrine that the animal becomes hyperthermic, as it cannot dissipate heat, and then this type of experiment cannot be undertaken.

Nonshivering thermogenic capacity can be determined in awake, non-anaesthetized animals Jansky et al. Principally, an acute stress response is induced by the injection itself, in addition to the direct norepinephrine-induced thermogenesis.

To improve the reproducibility of the measurements and decrease the number of animals required, anaesthetized animals can be studied. It is not possible to use inhalation anaesthetics as these inhibit brown fat activity Ohlson et al. The anaesthetized animal is placed in a small-volume measuring chamber at a temperature a few degrees higher than thermoneutral 33°C is needed for a mouse , in order to maintain its body temperature Golozoubova et al.

After an adequate period of measurement to estimate the basal metabolic rate, the animal is removed and injected with norepinephrine and returned to the chamber. The metabolic rate will rise and plateau Fig. The increase over basal is the nonshivering thermogenic capacity plus the pharmacological response to norepinephrine.

Basically, norepinephrine tests can therefore only be used to compare the difference in magnitude of the response between different conditions e. g warm- and cold-acclimated animals ; the absolute magnitude of nonshivering thermogenesis cannot be obtained by this method in itself.

It is important to distinguish between adrenergic thermogenesis and nonshivering thermogenesis. is a thermoregulatory thermogenesis. In general, this is probably not the case. It is no surprise that different organs display increased oxygen consumption thermogenesis when stimulated with norepinephrine.

In these organs, the cognate metabolic processes are stimulated, and any such stimulation leads to thermogenesis. Thus, norepinephrine stimulation of the salivary gland leads to increased oxygen consumption Terzic and Stoji, , as does stimulation of the liver Binet and Claret, These reactions have never been discussed to represent thermoregulatory thermogenesis; the heat is simply a by-product of the increased metabolism related to increased secretion, etc.

Only because muscle is traditionally discussed as being a thermogenic organ are similar adrenergically induced responses in muscle discussed as representing a form of thermoregulatory thermogenesis. Importantly, these brown-fat-independent types of adrenergic thermogenesis have never been shown to be adaptive.

This means that they are not recruited during acclimation to cold or adaptation to diet, and they are therefore not part of a thermoregulatory process.

Particularly in humans, there are many results from studies using infusions of adrenergic agents and measurements of oxygen consumption Blaak et al. These studies are, for the reasons stated above, probably not relevant for the type of thermogenesis discussed here, i.

thermoregulatory nonshivering thermogenesis or diet-induced thermogenesis. To our knowledge, there are no indications that this thermogenesis is adaptive. Additionally, there is the problem that the adrenergic concentrations achieved during infusion, particularly in humans, may be so low that only a hormonal action of adrenergic agonists is induced; i.

the levels may not be high enough to reach the postsynaptic areas in a sufficiently high concentration. In that case, brown adipose tissue may not be stimulated at all. The problem with the pharmacological response to norepinephrine can to some extent be overcome by using a specific β 3 -adrenergic agonist, notably CL, As β 3 -adrenergic receptors are only found in high density in adipose tissues, and as white adipose tissue is nearly inert with respect to oxygen consumption, the response seen would mainly emanate from brown adipose tissue, i.

However, the response may not represent the true capacity of brown adipose tissue because β 3 - and β 1 -adrenoreceptors may be needed to elicit the total β-adrenergic response, and there may be an α-adrenergic component Mohell et al.

Thus, only with norepinephrine is it certain that the entire thermogenic response is induced. Metabolic chambers measure the rate of oxygen consumption, and the outcome is thus in litres of oxygen per unit time. This is an approximation of the total heat production but, because the thermal equivalent of an oxygen molecule is different when carbohydrate or fat is combusted, conversion factors depending on the respiratory quotient should be used to convert the oxygen consumption values to energy W.

This is particularly important if the food composition is changed from carbohydrate to fat or during day-and-night measurements when the animals change from burning a mixed diet active phase to burning stored fat inactive phase.

The problems occurring by expressing metabolism per kg body weight. The animals symbolized have similar amounts of normal tissue black but different amounts of white adipose tissue grey.

Thus, to express metabolic rates per body weight or to any power of body weight leads to misleading conclusions. In studies of all types of metabolism, there is one major difficulty in interpretation and representation of the results: the denominator or the divisor, i.

how the results should be expressed. If the animals are of the same size and body composition, there is no problem, but very often this is not the case.

It may initially seem natural to express metabolism per gram body weight; however, in reality, animals are often studied that have become obese, e. due to a diet intervention or a genetic alteration. Such animals may have identical amounts of active lean tissue but are carrying expanded amounts of lipid around in their white adipose tissue Fig.

Lipid as a chemical is totally metabolically inert, and in no way contributes to metabolism. However, if the metabolic rate is expressed per gram body weight, and one animal carries extra weight in the form of lipid, the metabolic rate expressed in this way will appear smaller in the obese animal.

This is evidently not an adequate description. By contrast, if a treatment leads to leanness, the lipid carried around is less, the divisor is smaller and thus we have an explanation for leanness: enhanced thermogenesis Fig. Although these considerations would seem banal, the literature overflows with results calculated this way and conclusions based on these results.

The problem has been repeatedly addressed, but still seems to persist Himms-Hagen, ; Butler and Kozak, In an apparently more advanced way, metabolic rates and thermogenic capacities can be expressed per gram body weight raised to some power.

Most often the conversion is to grams raised to the power 0. Firstly, evidently this in no way eliminates the problem discussed above; lipid is still inert even if raised to any power.

Secondly, the power 0. mice and elephants. It turns out that the metabolism increases in proportion to the body weight to the power 0. For mathematical reasons, the power raising makes nearly no difference if, for example, mice with only somewhat different body weights are compared, and it should therefore only be used for comparisons between species.

Occasionally, the power 0. This is the geometrical relationship between the surface area and the volume weight of a sphere or cube.

The power relationship is of significance if thermal balance is discussed — but to use it to express rates of metabolism implies that all metabolism is due to heat loss to the surroundings, which is of course not the case.

The difference between the powers 0. What, then, is the solution to the dilemma of the divisor? The easiest — and in most circumstances most correct — solution is simply to give the results as per animal.

A more sophisticated, and on occasion advantageous, solution is to express the rate per gram lean body mass. Even to express the metabolic rates per gram lean mass assumes that all lean mass in the body has an equal metabolic rate.

This is not the case; therefore, although lean mass is a better approximation, it is not without its own problems. After all, if the modification studied should be causative of the development of obesity or protection against obesity , the altered metabolic rate should be present before the new phenotype becomes evident.

Brown adipose tissue is an admirable defence mechanism against cold. It has an impressively high oxidative capacity and thermogenic activity per gram of tissue and provides chronically cold-exposed mammals with a comfortable means of defending body temperature.

As pointed out above, in its absence, shivering will function but shivering is notably less comfortable than nonshivering thermogenesis and will impose restrictions on the animal's freedom of movement. Some 30 years ago, it was observed that a nonshivering thermogenic capacity could also be recruited by exposing rodents to so-called cafeteria diets or, later, to high-fat diets Rothwell and Stock, The mechanism of recruitment of brown adipose tissue under these conditions has not been clarified but it presumably involves activation of the sympathetic nervous system either directly by components in the diet as has been the general view or secondarily to the developing obesity as such.

It was proposed that animals that could develop brown adipose tissue in this way could use its thermogenic capacity to combust excess energy in the diet and thus not become as obese as otherwise expected.

Extensive studies by many groups have supported this view Cannon and Nedergaard, but see Maxwell et al. The magnitude of the increase in metabolic rate induced by injected norepinephrine is enhanced following dietary treatment, in a manner similar to that following cold acclimation i.

classical nonshivering thermogenesis Rothwell and Stock, ; Feldmann et al. Given their lack of BAT, it seems surprising then that muscle NST, or a combination of muscle NST and shivering, is sufficient to allow many birds to maintain very high 42°C T b even during cold exposure.

In cold-acclimated ducklings skeletal-muscles were identified as the major site of NST Duchamp and Barre, The fact that muscle NST seems more efficient in birds might be partially related to the better insulation of feathers in comparison with mammalian hair Aschoff, While birds can decrease their conductance enormously during cold exposure due the air trapped in the rigid feather structure, mammalian hair is softer and less suitable to trap air as an insulation barrier McNab, However, we suggest that there is another main reason for a lack of selective advantages of a BAT-like tissue in birds, which—to our knowledge—has never been considered before: skeletal muscles in birds already reach metabolic rates that are at least twice as high as in exercising small mammals, and can be as high as 8—18 times BMR Butler et al.

The rate-limiting step causing this difference between mammals and birds is the much greater capacity of avian skeletal muscles to take up circulating fatty acids reviewed in Jenni-Eiermann, It seems logical then that placental mammals, possessing BAT, would much benefit from enhanced fatty acid import, compared with skeletal muscle cells.

This is indeed ensured by the function of lipoprotein lipase, which, along with other enzymes, allows the massive import of fatty acids into BAT during thermogenesis at significantly higher rates than into skeletal muscle cells of placental mammals Heldmaier et al.

Interestingly, when the capacity of fatty acid import into muscle cells was increased by overexpression of lipoprotein lipase in transgenic mice, this improved cold resistance—independent from BAT thermogenesis—and elevated muscular fatty acid oxidation Jensen et al. As noted by Jensen et al.

Arguably, these differences in fuel import capacity into thermogenic tissues may well-explain the absence of BAT in birds, as well as the lower thermogenic capacity of marsupials and monotremes.

In summary, it seems that muscle NST may have been an important step in the evolution of endothermy. Endothermy is clearly facilitated by increasing mitochondrial membrane surface Else and Hulbert, and activity of the sodium-potassium pump, which is the greatest contributor to BMR Clarke et al.

However, apart from shivering, muscle NST via SERCA ATP hydrolysis was probably the first metabolic pathway in mammals solely used for thermogenesis. Interestingly, after mixed support for this model from smaller studies over the last decades, strong evidence for the aerobic capacity model comes from a recent comprehensive phylogenetically informed study ranging from fish and amphibians to birds and mammals, which shows that there is in fact a positive correlation between maximum and resting metabolic rates in mammals, and that this pattern is a result of natural selection Nespolo et al.

These findings again point to an important role of enhanced muscle function and metabolism for the emergence of endothermy. One of the reasons why the importance of muscle NST may have been underestimated in the past but see, e.

In contrast, activation of UCP1-mediated NST occurs prior to the onset of shivering Böckler and Heldmaier, which makes it easier to identify as a separate mechanism.

However, even NST in BAT can also occur simultaneously with shivering thermogenesis Böckler and Heldmaier, Arguably then, the evolution of endothermy was not characterized by switches from one to another, possibly improved, metabolic pathway.

Instead it seems that increasing levels of endothermy were achieved by recruiting additional mechanisms of thermogenesis to muscular work during locomotion, including specialized shivering thermogenesis, increases in mitochondrial density and membrane leakage, increases in sodium-potassium pump activity, shifts in SERCA activity toward NST.

Highly endothermic mammals living in cold environments apparently can use all of these mechanisms simultaneously. There are several possible selective advantages to this last evolutionary step, the additional recruitment of UCP1-mediated NST.

As already pointed out previously Rowland et al. Further, we suggest that the evolution of BAT in addition to muscle NST was related to heterothermy being predominant among early endothermic mammals.

This is because, in comparison with large muscles, a small dedicated thermogenic tissue such as BAT is much more suited to rapidly warm up and escape limiting Arrhenius effects of low tissue temperature during hibernation and torpor in harsh habitats.

Finally, we argue that additional mechanisms for NST are not required by animals that have enhanced capacities to fuel muscle NST by high rates of fatty acid import. Such a group of endotherms are birds, which probably evolved this superior fuel transport capacity as an adaptation to flight.

This would explain why birds have high endothermic capacities, despite the absence of BAT. JN wrote the first draft of the manuscript. All authors added text, discussed, and edited the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Understanding non-shivering thermogenesis of Physiological Anthropology volume Understanding non-shivering thermogenesisArticle number: 11 Nutritional analysis software this Underxtanding. Metrics Undfrstanding. The physiological function of non-shivering thermogenesis NST has been non-shiveribg in recent years, and some studies non-shuvering Pre-workout snacks the Understanding non-shivering thermogenesis of NST with respect to human cold adaptation. The present study aimed to clarify individual and seasonal variations in NST that occurred as a result of mild cold exposure. Seventeen male university students participated in the present study during summer and winter. The climate chamber used was programmed so that ambient temperature dropped from 28°C to 16°C over an min period. Physiological parameters of test subjects were recorded during the experiments.

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