How murine models of human disease and immunity are influenced by housing temperature and mild thermal stress.

At the direction of The Guide and Use of Laboratory Animals, rodents in laboratory facilities are housed at ambient temperatures between 20°C and 26°C, which fall below their thermoneutral zone (TNZ). TNZ is identified as a range of ambient temperatures that allow an organism to regulate body temperature without employing additional thermoregulatory processes (e.g. metabolic heat production driven by norepinephrine), thus leading to mild, chronic cold stress. For mice, this chronic cold stress leads to increased serum levels of the catecholamine norepinephrine, which has direct effects on various immune cells and several aspects of immunity and inflammation. Here, we review several studies that have revealed that ambient temperature significantly impacts outcomes in various murine models of human diseases, particularly those in which the immune system plays a major role in its pathogenesis. The impact of ambient temperature on experimental outcomes raises questions regarding the clinical relevance of some murine models of human disease, since studies examining rodents housed within thermoneutral ambient temperatures revealed that rodent disease pathology more closely resembled that of humans. Unlike laboratory rodents, humans can modify their surroundings accordingly - by adjusting their clothing, the thermostat, or their physical activity - to live within the appropriate TNZ, offering a possible explanation for why many studies using murine models of human disease conducted at thermoneutrality better represent patient outcomes. Thus, it is strongly recommended that ambient housing temperature in such studies be consistently and accurately reported and recognized as an important experimental variable.

Thermal performance curve of endurance running at high temperatures in deer mice.

The impacts of warming temperatures associated with climate change on performance are poorly understood in most mammals. Thermal performance curves are a valuable means of examining the effects of temperature on performance traits, but they have rarely been used in endotherms. Here, we examined the thermal performance curve of endurance running capacity at high temperatures in the deer mouse (Peromyscus maniculatus). Endurance capacity was measured using an incremental speed test on a treadmill, and subcutaneous temperature in the abdominal region was measured as a proxy for body temperature (Tb). Endurance time at 20°C was repeatable but varied appreciably across individuals, and was unaffected by sex or body mass. Endurance capacity was maintained across a broad range of ambient temperatures (Ta) but was reduced above 35°C. Tb during running varied with Ta, and reductions in endurance were associated with Tb greater than 40°C when Ta was above 35°C. At the high Ta that limited endurance running capacity (but not at lower Ta), Tb tended to rise throughout running trials with increases in running speed. Metabolic and thermoregulatory measurements at rest showed that Tb, evaporative water loss and breathing frequency increased at Ta of 36°C and above. Therefore, the upper threshold temperatures at which endurance capacity is impaired are similar to those inducing heat responses at rest in this species. These findings help discern the mechanisms by which deer mice are impacted by warming temperatures, and provide a general approach for examining thermal breadth of performance in small mammals.

Mediterranean songbirds show pronounced seasonal variation in thermoregulatory traits.

Addressing the patterns of variation in thermal traits is crucial to better predict the potential effects of climate change on organisms. Here, we assessed seasonal (winter vs summer) adjustments in key thermoregulatory traits in eight Mediterranean-resident songbirds. Overall, songbirds increased whole-animal (by 8%) and mass-adjusted (by 9%) basal metabolic rate and decreased (by 56%) thermal conductance below the thermoneutral zone during winter. The magnitude of these changes was within the lower values found in songbirds from northern temperate areas. Moreover, songbirds increased (by 11%) evaporative water loss within the thermoneutral zone during summer, while its rate of increase above the inflection point of evaporative water loss (i.e., the slope of evaporative water loss versus temperature) decreased by 35% during summer - a value well above that reported for other temperate and tropical songbirds. Finally, body mass increased by 5% during winter, a pattern similar to that found in many northern temperate species. Our findings support the idea that physiological adjustments might enhance the resilience of Mediterranean songbirds to environmental changes, with short-term benefits by saving energy and water under thermally stressful conditions. Nevertheless, not all species showed the same patterns, suggesting different strategies in their thermoregulatory adaptations to seasonal environments.

Temperature determines the shift of thermal neutral zone and influences thermogenic capacity in striped hamsters.

The thermoneutral zone (TNZ) reflects the adaptation of mammals to their natural habitat. However, it remains unclear how TNZ shifts in response to variations in ambient temperature. To test the hypothesis that ambient temperature plays a key role in determining TNZ variations between seasons, we measured metabolic rate, body temperature, and cytochrome c oxidase (COX) activity of several visceral organs in striped hamsters (Cricetulus barabensis) either acclimated to semi-natural conditions over a year, or subjected to a gradual decrease in mean temperature from 30 ± 1°C to -15 ± 1°C. The TNZ range in striped hamsters differed seasonally, with a wider TNZ and a lower lower-critical temperature in winter compared to summer. The hamsters showed a considerable leftward shift of lower-critical temperature from 30°C to 20°C after the ambient temperature of acclimation from 30°C down to -15°C, whereas the upper-critical temperature of TNZ remained fixed at 32.5°C. The resting metabolic rate in thermoneutral zone (RMRt), nonshivering thermogenesis (NST), and COX activity of brown adipose tissue, liver, skeletal muscle, brain, and kidneys, increased significantly in hamsters acclimated at lower ambient temperatures. Following acute exposure to 5°C and -15°C, hamsters acclimated to 32.5°C had significantly lower maximal NST and lower serum thyroid tri-iodothyronine (T3 ) levels compared to those kept at 23°C. These findings suggest that acclimation to the upper-critical temperature of TNZ impairs the hamsters' thermogenic capacity to cope with extreme cold temperature. Reduced ambient temperature was mainly responsible for the leftward shift of TNZ in striped hamsters, which reflects the adaptation to cold environments.

A survey on the use of rugs in Australian horses.

The practice of horse rugging has important implications for horse welfare and performance, but in Australia, rugging practices have not been properly documented. The objective of this study was to obtain an understanding of Australian horse rugging practices. An online survey reviewed the management of 2659 Australian horses over 12 months. Of the reported horses a total of 84.8% were rugged, although most owners (69.5%) indicated that they were unsure whether horses needed to be rugged at all. Rugging was felt by 59.8% of owners to be a requirement for horses in competition. Riding and competition were significantly associated with the use of rugs. Nearly all respondents (89.0%) felt that 'over-rugging' was a concern. However, 4.8% of owners would use up to 4 rugs at any one time on their horse and 21.4% of horses were still rugged in temperatures above 20°C in Australia. Many Australian horse owners (42.8%) also believe that horses feel cold if they are not rugged. Anthropomorphism when it comes to rugging horses cannot be justified as the horse has a much wider thermoneutral zone (TNZ) than humans. Australian climate, owner opinions, equestrian discipline and whether a horse is used for riding influence Australian horse rugging practices. However, current practices are based on limited available research and are not necessarily to the benefit of the horse. The major limitation was that the survey likely attracted respondents who are interested in the topic creating a self-selection bias.

The metabolic upper critical temperature of the human thermoneutral zone.

INTRODUCTION: The thermoneutral zone (TNZ) defines the range of ambient temperatures at which resting metabolic rate is at a minimum without sensible dry heat loss; the body not needing to defend its core temperature. The TNZ has been defined in a number of species yet surprisingly, in humans only its lower limit has been well characterised; indeed, it is not yet clear if there is an upper limit at which metabolic rate increases. AIM: To evaluate the evidence for a metabolic upper critical temperature to the thermoneutral zone in humans. METHODS: We synthesised current evidence about an upper limit to the human TNZ, highlighting the contradictions in the literature, and then discussed likely explanations for those contradictions. RESULTS: The data from relevant studies differ in terms of whether they indicate that the TNZ has an upper limit, and this was related to the fundamental type of heat exposure protocol employed. Those studies showing evidence for an upper limit associated that limit with a wide range of temperatures. CONCLUSIONS: We offer suggestions for future studies that should clarify the presence/absence of an upper limit to the TNZ and if present, where it lies.

Phenotypic plasticity to chronic cold exposure in two species of Peromyscus from different environments.

Effective thermoregulation is important for mammals, particularly those that remain winter-active. Adjustments in thermoregulatory capacity in response to chronic cold can improve capacities for metabolic heat production (cold-induced maximal oxygen consumption, [Formula: see text]), minimize rates of heat loss (thermal conductance), or both. This can be challenging for animals living in chronically colder habitats where necessary resources (i.e., food, O2) for metabolic heat production are limited. Here we used lowland native white-footed mice (Peromyscus leucopus) and highland deer mice (P. maniculatus) native to 4300 m, to test the hypothesis that small winter-active mammals have evolved distinct cold acclimation responses to tailor their thermal physiology based on the energetic demands of their environment. We found that both species increased their [Formula: see text] after cold acclimation, associated with increases in brown adipose tissue mass and expression of uncoupling protein 1. They also broadened their thermoneutral zone to include lower ambient temperatures. This was accompanied by an increase in basal metabolic rate but only in white-footed mice, and neither species adjusted thermal conductance. Unique to highland deer mice was a mild hypothermia as ambient temperatures decreased, which reduced the gradient for heat loss, possibly to save energy in the chronically cold high alpine. These results highlight that thermal acclimation involves coordinated plasticity of numerous traits and suggest that small, winter-active mammals may adjust different aspects of their physiology in response to changing temperatures to best suit their energetic and thermoregulatory needs.

Temperature and exudativory as drivers of the marmoset (Callithrix spp.) daily activity period.

Primates are affected by fluctuations in ambient temperatures, mostly through thermoregulatory costs and changes in the availability of food. In the present study, we investigate whether the ambient temperature and proxies of food availability affect the activity period of marmosets (Callithrix spp.). We predicted that: (i) at colder sites, marmosets would spend more time at sleeping sites; (ii) midday resting bouts would be longer at hotter sites; (iii) the onset/cessation of activity and resting behavior at midday would be more closely related to temperature than food availability, and (iv) highly exudativorous groups would have higher total levels of resting. We compiled data on the onset and cessation of activity and the time spent resting at midday from seven marmoset studies from sites with a wide range of temperatures. We used generalized linear mixed models to verify the relationship between the dependent variables (lag between dawn and the onset of activities, lag between cessation of activities and dusk, and proportion of resting during midday) and the minimum and maximum temperatures at the respective study sites, together with proxies of food availability (exudativory rates, the amount of habitat available per individual, and net primary productivity) using each sample month as a sampling unit and the identity of the study as a categorical random factor. At colder sites and during colder months, the marmosets left sleeping trees later in the morning and ceased their activities earlier, while at hotter sites and during hotter months, they spent more time resting during midday. More exudativorous groups become active later in the morning, but also ceased their activities later. The abundance of food did not affect the timing of activities. We provide evidence that both low and high temperatures affect marmosets' activities, and that their activity period appears to be more influenced by the thermal environment than food availability.

The joint effect of micro- and macro-climate on the thermoregulation and heat dissipation of two African mole-rat (Bathyergidae) sub-species, Cryptomys hottentotus mahali and C. h. pretoriae.

The effect of the macro- and microclimate on small mammal thermoregulation in the past has been studied independently instead of investigating the dual effect of both the components. This study addresses this dearth in knowledge by exploring the dual effect of both micro- and macro-climate on the thermoregulatory responses of two subterranean rodent species belonging to the family Bathyergidae, namely the more arid dwelling Mahali mole-rat (Cryptomys hottentotus mahali) and less arid dwelling Highveld mole-rat (C. h. pretoriae). Open flow through respirometry was used to quantify resting metabolic rates (RMR), evaporative water loss (EWL), core body temperature (Tb), the ratio between the evaporative heat loss and metabolic heat production (EHL/MHP: evaporative cooling capacity) and conductance (Cdry) over a range of increasing ambient temperatures (Ta; 20-42 °C). Furthermore, RMR, EWL, Tb, EHL/MHP and Cdry were measured at the mole-rat's thermal maxima (43 °C). At cooler temperatures, the arid-dwelling C. h. mahali possesses a broader thermoneutral zone (~5 °C; 27.2-32.1 °C), while C. h. pretoriae possess a single thermoneutral point (33.6 °C). This is in response to the greater selection pressure to conserve energy in the more arid regions inhabited by C. h. mahali. Contrastingly, at hotter temperatures, there were no significant thermoregulatory differences in EWL, EHL/MHP or Cdry responses between the two sub-species, as expected due to the limitations bestowed by the buffered microclimates (burrow systems). Thus, neither macro-climate, nor micro-climate singularly moulds the thermoregulatory adaptations, but rather, it appears to be a combined effect from both climates. Other small endotherms may share this dual response, and therefore, it is crucial to incorporate the effect of both macro- and microclimates into future climate models when determining the ecological capabilities and persistence of a species.

The cardio-respiratory effects of passive heating and the human thermoneutral zone.

The thermoneutral zone (TNZ) defines the range of ambient temperatures at which resting metabolic rate (MR) is at a minimum. While the TNZ lower limit has been characterized, it is still unclear whether there is an upper limit, that is, beyond which MR during rest increases, and if so, what physiological upregulations explain this. We take the first step to fill this knowledge gap by measuring MR and multiple physiological variables in participants exposed to ambient heat stress while resting. Thirteen participants were exposed for an hour to 28℃-50% relative humidity (RH) air, and both 40 and 50℃ each in 25% RH and humid (50% RH) conditions. Core and skin temperatures, blood pressure, sweat-, heart-, and breathing-rate, minute ventilation, and movement levels were recorded throughout each condition. MR increased 35% (p = .015) during exposure to 40℃-25% RH compared to baseline and a further 13% (p = .000) at in 50℃-50%RH. This was not explained by increased fidgeting (p = .26), suggesting physiological upregulation. However, while greater heat stress invoked increases in heart rate (64%, p = .000), minute ventilation (78%, p = .000), and sweat rate (74%. p = .000) when comparing 50℃-50% RH with baseline, the exact size of their relative energy cost is unclear and, therefore, so is their contribution to this increase in MR. Our study shows clear evidence that resting MR increases in humans at high temperature-there is a metabolic upper critical temperature, at least as low as 40℃. Further studies should pinpoint this value and fully explain this increased MR.

Energy Consumption of Young Military Working Dogs in Pre-Training in Germany.

Many factors have specific effects, in varying degrees of intensity, on the metabolic energy requirements of working dogs. Appropriate energy supply adjusted to the requirements of military working dogs at pre-training is a basic prerequisite for working dogs, so they are fully able to exercise. Therefore, more knowledge obtained under standardized conditions would be advantageous. Twenty intact Belgian Shepherds var. Malinois at the age of 12 months were accompanied for four weeks during pre-training (odour detection, obedience training, and protection work) as military working dogs (MWDs) in Germany (ambient temperature about 7.8 °C), and the amount of energy intake was evaluated. To assess changes in body constitution, body weight and shoulder height were measured, and the thickness of subcutaneous fat tissue (SCF), and of Musculus sacrocaudalis dorsalis lateralis (MSCDL), were recorded via ultrasound. Energy intake amounted to, on average, 244 ± 34 kcal/kg body weight (BW)0.75 daily. Increases in body weight, shoulder height, and thickness of the MSCDL, as well as a reduction of SCF thickness lying on the MSCDL, were observed. Changes of body constitution might be attributed to training-induced muscle growth and physiological growth in size. In addition to training intensity, influences of ambient temperature and physiological body growth seemed to be important contributing factors in the supply of energy for MWDs during pre-training.

Thermoregulation in Malayan sun bears (Helarctos malayanus) and its consequences for in situ conservation.

Thermoregulation in Malayan sun bears is not fully understood. Therefore, in this study the effect of meteorological variables on both behavioural and autonomic thermoregulatory mechanisms in sun bears was examined in order to identify temperature thresholds for the activation of various thermoregulatory mechanisms. Infrared thermography was used to non‒invasively determine body surface temperature (TS) distribution in relation to ambient temperature (TA) and to determine the thermoneutral zone (TNZ) of sun bears. Thermographic measurements were performed on 10 adult sun bears at TA between 5 °C and 30 °C in three European zoos. To assess behaviours that contribute to thermoregulation, nine adult sun bears were observed at TA ranging from 5 °C to 34 °C by instantaneous scan sampling in 60 s intervals for a total of 787 h. Thermographic measurements revealed that the TNZ of sun bears lies between 24 °C and 28 °C and that heat is equally dissipated over the body surface. Behavioural data showed that behaviours related to thermoregulation occurred in advance of energetically costly autonomic mechanisms, and were highly correlated with TA and solar radiation. While the temperature threshold for the onset of thermoregulatory behaviours below the TNZ lies around 15 °C, which is well below the lower critical temperature (TLC) assessed by thermography, the onset for behaviours to prevent overheating occurred at 28 °C, which was closer to the estimated upper critical temperature (TUC) of sun bears. These findings provide useful data on the thermal requirements of sun bears with respect to the species potential to cope with the effects of climate change and deforestation which are occurring in their natural range. Furthermore, these results may have important implications for the care and welfare of bears in captivity and should be taken into consideration, when designing and managing facilities.

Sex-specific alterations in whole body energetics and voluntary activity in heterozygous R163C malignant hyperthermia-susceptible mice.

Malignant hyperthermia (MH) is characterized by induction of skeletal muscle hyperthermia in response to a dysregulated increase in myoplasmic calcium. Although altered energetics play a central role in MH, MH-susceptible humans and mouse models are often described as having no phenotype until exposure to a triggering agent. The purpose of this study was to determine the influence of the R163C ryanodine receptor 1 mutation, a common MH mutation in humans, on energy expenditure, and voluntary wheel running in mice. Energy expenditure was measured by indirect respiration calorimetry in wild-type (WT) and heterozygous R163C (HET) mice over a range of ambient temperatures. Energy expenditure adjusted for body weight or lean mass was increased (P < .05) in male, but not female, HET mice housed at 22°C or when housed at 28°C with a running wheel. In female mice, voluntary wheel running was decreased (P < .05) in the HET vs WT animals when analyzed across ambient temperatures. The thermoneutral zone was also widened in both male and female HET mice. The results of the study show that the R163C mutations alters energetics even at temperatures that do not typically induce MH.

Mouse Thermoregulation: Introducing the Concept of the Thermoneutral Point.

Human and mouse thermal physiology differ due to dissimilar body sizes. Unexpectedly, in mice we found no ambient temperature zone where both metabolic rate and body temperature were constant. Body temperature began increasing once cold-induced thermogenesis was no longer required. This result reproduced in male, female, C57BL/6J, 129, chow-fed, diet-induced obese, and ob/ob mice as well as Trpv1-/-;Trpm8-/-;Trpa1-/- mice lacking thermal sensory channels. During the resting-light phase, the energy expenditure minimum spanned ∼4°C of ambient temperature, whereas in the active-dark phase it approximated a point. We propose the concept of a thermoneutral point (TNP), a discrete ambient temperature below which energy expenditure increases and above which body temperature increases. Humans do not have a TNP. As studied, the mouse TNP is ∼29°C in light phase and ∼33°C in dark phase. These observations inform how thermoneutrality is defined and how mice are used to model human energy physiology and drug development.

Body surface temperature responses to food restriction in wild and captive great tits.

During winter at temperate and high latitudes, the low ambient temperatures, limited food supplies and short foraging periods mean small passerines show behavioural, morphological and physiological adaptations to reduce the risk of facing energy shortages. Peripheral tissues vasoconstrict in low ambient temperatures to reduce heat loss and cold injury. Peripheral vasoconstriction has been observed with food restriction in captivity but has yet to be explored in free-ranging animals. We experimentally food restricted both wild and captive great tits (Parus major) during winter months and measured surface temperatures of the bill and eye region using thermal imaging, to investigate whether birds show rapid local heterothermic responses, which may reduce their thermoregulatory costs when facing a perceived imminent food shortage. Our results of a continuously filmed wild population showed that bill temperature was immediately reduced in response to food restriction compared with when food was available ad libitum, an apparent autonomic response. Such immediacy implies a 'pre-emptive' response before the bird experiences any shortfalls in energy reserves. We also demonstrate temporal variation in vasoconstriction of the bill, with bill temperature gradually rising throughout the food restriction after the initial drop. Eye-region temperature in the wild birds remained at similar levels throughout food restriction compared with unrestricted birds, possibly reflecting the need to maintain steady circulation to the central nervous and visual systems. Our findings provide evidence that birds selectively allow the bill to cool when a predictable food supply is suddenly disrupted, probably as a means of minimising depletion of body reserves for a perceived future shortage in energy.

Small Tropical Mammals Can Take the Heat: High Upper Limits of Thermoneutrality in a Bornean Treeshrew.

Tropical ectotherms are generally believed to be more vulnerable to global heating than temperate species. Currently, however, we have insufficient knowledge of the thermoregulatory physiology of equatorial tropical mammals, particularly of small diurnal mammals, to enable similar predictions. In this study, we measured the resting metabolic rates (via oxygen consumption) of wild-caught lesser treeshrews (Tupaia minor, order Scandentia) over a range of ambient temperatures. We predicted that, similar to other treeshrews, T. minor would exhibit more flexibility in body temperature regulation and a wider thermoneutral zone compared with other small mammals because these thermoregulatory traits provide both energy and water savings at high ambient temperatures. Basal metabolic rate was on average 1.03±0.10 mL O2 h-1 g-1, which is within the range predicted for a 65-g mammal. We calculated the lower critical temperature of the thermoneutral zone at 31.0°C (95% confidence interval: 29.3°-32.7°C), but using metabolic rates alone, we could not determine the upper critical temperature at ambient temperatures as high as 36°C. The thermoregulatory characteristics of lesser treeshrews provide a means of saving energy and water at temperatures well in excess of their current environmental temperatures. Our research highlights the knowledge gaps in our understanding of the energetics of mammals living in high-temperature environments, specifically in the equatorial tropics, and questions the purported lack of variance in the upper critical temperatures of the thermoneutral zone in mammals, emphasizing the importance of further research in the tropics.

Desempenho e termorregulação de porcas lactantes alojadas em diferentes localizações no interior de um galpão com sistema de resfriamento evaporativo em ambiente tropical / Performance and thermoregulation of lactating sows housed in different locations inside a shed with an evaporative cooling system in a tropical environment

The effects of housing lactating sows at different locations in a shed with evaporative cooling system (ECS) on their thermoregulation and reproductive and productive performance of the sow and the litter in summer were determined. 34 females were used in the three lines of cages at these locations: near the pad cooling; in the middle of the shed and near the exhaust fans. The air temperature and the temperature and humidity index (THI) were lower near the pad cooling (22.38ºC, 71.84) than the middle (24.56ºC, 74.82) and near the exhaust fans (25.00°C, 75.62). Respiratory rate, rectal and surface temperatures were lower in sows near the pad cooling (43.67 breaths.min -1 , 38.40°C; 29.51°C) than in the center (52.04 breaths.min -1 ; 38.48ºC; 32.02ºC) and near the exhaust fans (56.38 breaths.min-1, 38.93ºC; 32.52ºC). The backfat thickness, the weaning-estrus interval and daily average consumption of the sows, number of weaning piglets, corporal mass and daily average gain of the piglets were not influenced by the location of housing in the shed. Lactating sows housed in the middle and near the exhaust fans in the ECS presented increased thermoregulation physiological variables, however, this did not impair the performance.(AU)

Brown adipose tissue plays thermoregulatory role within the thermoneutral zone in Mongolian gerbils (Meriones unguiculatus).

Brown adipose tissue (BAT) plays an important role in thermoregulation and many metabolic processes in small mammals, especially in cold adaptation. However, in warm adaptation, ambient temperature cannot directly activate BAT by sympathetic nervous system. Mongolian gerbils exhibit a wider thermoneutral zone (26.5-38.9 °C). We hypothesized that BAT atrophied near the lower critical temperature and further atrophied near the upper critical temperature. Male gerbils were acclimated to 23 °C, 27 °C or 37 °C, respectively, for 3 weeks. Results showed that regulatory non-shivering thermogenesis did not change in gerbils acclimated to 27 °C compared with 23 °C group, whereas it was reduced by 43.5% in gerbils acclimated to 37 °C. Bigger lipid droplet in BAT was observed in gerbils acclimated to 27 °C and 37 °C compared with 23 °C group, while the expression of uncoupling protein 1 and tyrosine hydroxylase was only reduced in gerbils acclimated to 37 °C. Further, thermoneutral acclimation did not change BAT thermogenesis by down-regulation of peroxisome proliferator-activated receptor gamma coactivator-1α, PR domain containing 16, peroxisome proliferator-activated receptor-α or peroxisome proliferator activated receptor-γ gene expression in BAT. In addition, body temperature was reduced in gerbils acclimated to 37 °C compared with 23 °C group, which was associated with a decreased resting metabolic rate and regulatory non-shivering thermogenesis. In conclusion, BAT does not atrophy near the lower critical temperature, whereas it atrophies near the upper critical temperature, suggesting that BAT may play thermoregulatory role within the TNZ in Mongolian gerbils.

The Utility of Forearm to Fingertip Skin Temperature Gradients During Measurements of Resting Energy Expenditure.

The measurement of resting energy expenditure (REE) is important to both human physiology and nutrition. There are several pre-conditions for the proper measurement of REE, but a key criterion is that it takes place in the thermoneutral zone (TNZ). Deciding whether a person is in his or her TNZ is not an easy task, and a suggested way forward is the monitoring of forearm to fingertip skin temperature gradients (FFG). In this commentary, we highlight our recent findings that FFG varies between individuals even when measured at a temperature within TNZ. Interestingly, FFG showed a consistent direct relationship with adjusted REE, in both cross-sectional and longitudinal study designs. In addition, we provide new findings that FFG is sensitive to small ambient temperature variations within the TNZ, in comparison to visual analogue scale (VAS)-derived subjective measures of thermal comfort. While further research is needed in this area, our view is measurements of FFG should be included in REE protocols. This would inform investigators on how their participants are responding to the ambient room temperature and also allow appropriate statistical adjustments in REE for between-group comparisons.

The thermoregulation system and how it works.

Heat exchange processes between the body and the environment are introduced. The definition of the thermoneutral zone as the ambient temperature range within which body temperature (Tb) regulation is achieved only by nonevaporative processes is explained. Thermoreceptors, thermoregulatory effectors (both physiologic and behavioral), and neural pathways and Tb signals that connect receptors and effectors into a thermoregulation system are reviewed. A classification of thermoeffectors is proposed. A consensus concept is presented, according to which the thermoregulation system is organized as a dynamic federation of independent thermoeffector loops. While the activity of each effector is driven by a unique combination of deep (core) and superficial (shell) Tbs, the regulated variable of the system can be viewed as a spatially distributed Tb with a heavily represented core and a lightly represented shell. Core Tb is the main feedback; it is always negative. Shell Tbs (mostly of the hairy skin) represent the auxiliary feedback, which can be negative or positive, and which decreases the system's response time and load error. Signals from the glabrous (nonhairy) skin about the temperature of objects in the environment serve as feedforward signals for various behaviors. Physiologic effectors do not use feedforward signals. The system interacts with other homeostatic systems by "meshing" with their loops. Coordination between different thermoeffectors is achieved through the common controlled variable, Tb. The term balance point (not set point) is used for a regulated level of Tb. The term interthreshold zone is used for a Tb range in which no effectors are activated. Thermoregulatory states are classified, based on whether: Tb is increased (hyperthermia) or decreased (hypothermia); the interthreshold zone is narrow (homeothermic type of regulation) or wide (poikilothermic type); and the balance point is increased (fever) or decreased (anapyrexia). During fever, thermoregulation can be either homeothermic or poikilothermic; anapyrexia is always a poikilothermic state. The biologic significance of poikilothermic states is discussed. As an example of practical applications of the concept presented, thermopharmacology is reviewed. Thermopharmacology uses drugs to modulate specific temperature signals at the level of a thermoreceptor (transient receptor potential channel).