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Despite many decades of research examining thermoregulatory responses under varying cold stresses in humans, very little is known about the variability in metabolic heat production and shivering activity. Here, we used a novel closed-loop mean skin temperature clamping technique with a liquid-conditioned suit to isolate the effects of mean skin temperature on the subjective evaluation of thermal sensation, heat production, shivering responses, and oxidative fuel selection in young, lean, and healthy men ( n = 12) and women ( n = 12). Our results showed a skin temperature-dependent increase in metabolic heat production (5.2 ± 1.2 kJ/min, 5.9 ± 1.5 kJ/min, and 7.0 ± 1.8 kJ/min with skin temperature maintained at 31 ± 0.1°C, 29 ± 0.2°C, and 27 ± 0.1°C, respectively; P < 0.0001) and shivering intensity in both men and women [0.6 ± 0.1% maximal voluntary contraction (MVC), 1.1 ± 0.4% MVC, and 2.5 ± 0.7% MVC, respectively; P < 0.0001], including sex-dependent differences in heat production at all three temperatures ( P < 0.005). Even when controlling for lean body mass and fat mass, sex differences persisted ( P = 0.048 and P = 0.004, respectively), whereas controlling for differences in body surface area eliminated these differences. Interestingly, there were no sex differences in the cold-induced change in thermogenesis. Despite clamping skin temperature, there was tremendous variability in the rate of heat production and shivering intensity. Collectively this data suggests that many of the interindividual differences in thermogenesis and shivering may be explained by differences in morphology and body composition.

Objectives: Soldier performance in the Arctic depends on planning and training, protective equipment, and human physiological limits. The purpose of this review was to highlight the span of current research on enhancing soldier effectiveness in extreme cold and austere environments., Methods: The practices of seasoned soldiers who train in the Arctic and cold-dwelling natives inform performance strategies. We provide examples of research and technology that build on these concepts., Results: Examples of current performance research include evaluation of equipment and tactics such as the bioenergetics of load carriage over snow in Norwegian exercises; Canadian field monitoring of hand temperatures and freezing cold injuries for better protection of manual dexterity; and Dutch predictive modeling of cold-wet work tolerances. Healthy young men can respond to cold with a substantial thermogenic response based on US and Canadian studies on brown adipose tissue and other mechanisms of non-shivering thermogenesis; the potential advantage of greater fat insulation is offset in obese unfit subjects by a smaller thermogenic response. Current physiological studies are addressing previously unanswered problems of cold acclimation procedures, thermogenic enhancement and regulation, and modulation of sympathetic activation, all of which may further enhance cold survival and expand the performance envelope., Conclusion: There is an inseparable behavioral component to soldier performance in the Arctic, and even the best equipment does not benefit soldiers who have not trained in the actual environment. Training inexperienced soldiers to performance limits may be helped with personal monitoring technologies and predictive models., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Stimulation of brown adipose tissue (BAT) thermogenesis in humans has emerged as an attractive target to improve metabolic health. Pharmacological stimulations targeting the β 3 -adrenergic receptor (β 3 -AR), the adrenergic receptor believed to mediate BAT thermogenesis, have historically performed poorly in human clinical trials. Here we report that, in contrast to rodents, human BAT thermogenesis is not mediated by the stimulation of β 3 -AR. Oral administration of the β 3 -AR agonist mirabegron only elicited increases in BAT thermogenesis when ingested at the maximal allowable dose. This led to off-target binding to β 1 -AR and β 2 -AR, thereby increasing cardiovascular responses and white adipose tissue lipolysis, respectively. ADRB2 was co-expressed with UCP1 in human brown adipocytes. Pharmacological stimulation and inhibition of the β 2 -AR as well as knockdown of ADRB1, ADRB2, or ADRB3 in human brown adipocytes all confirmed that BAT lipolysis and thermogenesis occur through β 2 -AR signaling in humans (ClinicalTrials.govNCT02811289)., Competing Interests: Declaration of Interests A.C.C. received funding from Eli Lilly, HLS Therapeutics, Janssen Inc., Novartis Pharmaceuticals Canada Inc., and Novo Nordisk Canada Inc. as a consultant. None of these commercial relationships are relevant to the present study. The remaining authors have declared that no conflict of interest exists related to the content of this manuscript., (Copyright © 2020 Elsevier Inc. All rights reserved.)

For humans to maintain a stable core temperature in cold environments, an increase in energy expenditure (EE) is required. However, little is known about how cold stimulus impacts energy balance as a whole, as energy intake (EI) has been largely overlooked. This review focuses on the current state of knowledge regarding how cold exposure (CE) impacts both EE and EI, while highlighting key gaps and shortcomings in the literature. Animal models clearly reveal that CE produces large increases in EE, while decreasing environmental temperatures results in a significant negative dose-response effect in EI (r=-.787, P<.001), meaning animals eat more as temperature decreases. In humans, multiple methods are used to administer cold stimuli, which result in consistent yet quantitatively small increases in EE. However, only two studies have measured ad libitum food intake in combination with acute CE in humans. Chronic CE (i.e., cold acclimation) studies have been shown to produce minimal changes in body weight, with an average compensation of ~126%. Although more studies are required to investigate how cold impacts EI in humans, results presented in this review warrant caution before presenting or considering CE as a potential adjunct to weight loss strategies., (© 2019 World Obesity Federation.)

Daily compensable cold exposure in humans reduces shivering by ~20% without changing total heat production, partly by increasing brown adipose tissue thermogenic capacity and activity. Although acclimation and acclimatization studies have long suggested that daily reductions in core temperature are essential to elicit significant metabolic changes in response to repeated cold exposure, this has never directly been demonstrated. The aim of the present study is to determine whether daily cold-water immersion, resulting in a significant fall in core temperature, can further reduce shivering intensity during mild acute cold exposure. Seven men underwent 1 h of daily cold-water immersion (14°C) for seven consecutive days. Immediately before and following the acclimation protocol, participants underwent a mild cold exposure using a novel skin temperature clamping cold exposure protocol to elicit the same thermogenic rate between trials. Metabolic heat production, shivering intensity, muscle recruitment pattern, and thermal sensation were measured throughout these experimental sessions. Uncompensable cold acclimation reduced total shivering intensity by 36% ( P = 0.003), without affecting whole body heat production, double what was previously shown from a 4-wk mild acclimation. This implies that nonshivering thermogenesis increased to supplement the reduction in the thermogenic contribution of shivering. As fuel selection did not change following the 7-day cold acclimation, we suggest that the nonshivering mechanism recruited must rely on a similar fuel mixture to produce this heat. The more significant reductions in shivering intensity compared with a longer mild cold acclimation suggest important differential metabolic responses, resulting from an uncompensable compared with compensable cold acclimation. NEW & NOTEWORTHY Several decades of research have been dedicated to reducing the presence of shivering during cold exposure. The present study aims to determine whether as little as seven consecutive days of cold-water immersion is sufficient to reduce shivering and increase nonshivering thermogenesis. We provide evidence that whole body nonshivering thermogenesis can be increased to offset a reduction in shivering activity to maintain endogenous heat production. This demonstrates that short, but intense cold stimulation can elicit rapid metabolic changes in humans, thereby improving our comfort and ability to perform various motor tasks in the cold. Further research is required to determine the nonshivering processes that are upregulated within this short time period.

Humans have inherited complex neural circuits which drive behavioral, somatic, and autonomic thermoregulatory responses to defend their body temperature. While they are well adapted to dissipate heat in warm climates, they have a reduced capacity to preserve it in cold environments. Consequently, heat production is critical to defending their core temperature. As in other large mammals, skeletal muscles are the primary source of heat production recruited in cold-exposed humans. This is achieved voluntarily in the form of contractions from exercising muscles or involuntarily in the form of contractions from shivering muscles and the recruitment of nonshivering mechanisms. This review describes our current understanding of shivering and nonshivering thermogenesis in skeletal muscles, from the neural circuitry driving their recruitment to the metabolic substrates that fuel them. The presence of these heat-producing mechanisms can be measured in vivo by combining indirect respiratory calorimetry with electromyography or biomedical imaging modalities. Indeed, much of what is known regarding shivering in humans and other animal models stems from studies performed using these methods combined with in situ and in vivo neurologic techniques. More recent investigations have focused on understanding the metabolic processes that produce the heat from both contracting and noncontracting mechanisms. 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., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Key Points: Muscle-derived thermogenesis during acute cold exposure in humans consists of a combination of cold-induced increases in skeletal muscle proton leak and shivering. Daily cold exposure results in an increase in brown adipose tissue oxidative capacity coupled with a decrease in the cold-induced skeletal muscle proton leak and shivering intensity. Improved coupling between electromyography-determined muscle activity and whole-body heat production following cold acclimation suggests a maintenance of ATPase-dependent thermogenesis and decrease in skeletal muscle ATPase independent thermogenesis. Although daily cold exposure did not change the fibre composition of the vastus lateralis, the fibre composition was a strong predictor of the shivering pattern evoked during acute cold exposure., Abstract: We previously showed that 4 weeks of daily cold exposure in humans can increase brown adipose tissue (BAT) volume by 45% and oxidative metabolism by 182%. Surprisingly, we did not find a reciprocal reduction in shivering intensity when exposed to a mild cold (18°C). The present study aimed to determine whether changes in skeletal muscle oxidative metabolism or shivering activity could account for these unexpected findings. Nine men participated in a 4 week cold acclimation intervention (10°C water circulating in liquid-conditioned suit, 2 h day -1 , 5 days week -1 ). Shivering intensity and pattern were measured continuously during controlled cold exposure (150 min at 4 °C) before and after the acclimation. Muscle biopsies from the m. vastus lateralis were obtained to measure oxygen consumption rate and proton leak of permeabilized muscle fibres. Cold acclimation elicited a modest 21% (P < 0.05) decrease in whole-body and m. vastus lateralis shivering intensity. Furthermore, cold acclimation abolished the acute cold-induced increase in proton leak. Although daily cold exposure did not change the fibre composition of the m. vastus lateralis, fibre composition was a strong predictor of the shivering pattern evoked during acute cold. We conclude that muscle-derived thermogenesis during acute cold exposure in humans is not only limited to shivering, but also includes cold-induced increases in proton leak. The efficiency of muscle oxidative phosphorylation improves with cold acclimation, suggesting that reduced muscle thermogenesis occurs through decreased proton leak, in addition to decreased shivering intensity as BAT capacity and activity increase. These changes occur with no net difference in whole-body thermogenesis., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)

In rodents, brown adipose tissue (BAT) plays an important role in producing heat to defend against the cold and can metabolize large amounts of dietary fatty acids (DFA). The role of BAT in DFA metabolism in humans is unknown. Here we show that mild cold stimulation (18 °C) results in a significantly greater fractional DFA extraction by BAT relative to skeletal muscle and white adipose tissue in non-cold-acclimated men given a standard liquid meal containing the long-chain fatty acid PET tracer, 14(R,S)-[ 18 F]-fluoro-6-thia-heptadecanoic acid ( 18 FTHA). However, the net contribution of BAT to systemic DFA clearance is comparatively small. Despite a 4-week cold acclimation increasing BAT oxidative metabolism 2.6-fold, BAT DFA uptake does not increase further. These findings show that cold-stimulated BAT can contribute to the clearance of DFA from circulation but its contribution is not as significant as the heart, liver, skeletal muscles or white adipose tissues., Competing Interests: The authors declare no competing financial interests.

Because the majority of cold exposure studies are constrained to short-term durations of several hours, the long-term metabolic demands of cold exposure, such as during survival situations, remain largely unknown. The present study provides the first estimates of thermogenic rate, oxidative fuel selection, and muscle recruitment during a 24-h cold-survival simulation. Using combined indirect calorimetry and electrophysiological and isotopic methods, changes in muscle glycogen, total carbohydrate, lipid, protein oxidation, muscle recruitment, and whole body thermogenic rate were determined in underfed and noncold-acclimatized men during a simulated accidental exposure to 7.5 °C for 12 to 24 h. In noncold-acclimatized healthy men, cold exposure induced a decrease of ∼0.8 °C in core temperature and a decrease of ∼6.1 °C in mean skin temperature (range, 5.4-6.9 °C). Results showed that total heat production increased by approximately 1.3- to 1.5-fold in the cold and remained constant throughout cold exposure. Interestingly, this constant rise in Ḣprod and shivering intensity was accompanied by a large modification in fuel selection that occurred between 6 and 12 h; total carbohydrate oxidation decreased by 2.4-fold, and lipid oxidation doubled progressively from baseline to 24 h. Clearly, such changes in fuel selection dramatically reduces the utilization of limited muscle glycogen reserves, thus extending the predicted time to muscle glycogen depletion to as much as 15 days rather than the previous estimates of approximately 30-40 h. Further research is needed to determine whether this would also be the case under different nutritional and/or colder conditions., (Copyright © 2016 the American Physiological Society.)

The effects of epigallocatechin-3-gallate (EGCG) and caffeine on non-shivering thermogenesis (NST) during cold exposure is unknown. The purpose of the present study was to quantify the effects of co-ingesting EGCG and caffeine on the thermogenic responses of a 3 h cold exposure. A total of eight healthy males were exposed to mild cold, using a liquid-conditioned suit perfused with 158C water, on two occasions and consumed a placebo or an extract of 1600 mg of EGCG and 600 mg of caffeine (Green tea). Thermic, metabolic and electromyographic measurements were monitored at baseline and during the cold exposure. Results showed that the AUC of shivering intensity over the cold exposure period was reduced by approximately 20% in the Green tea (266 (SEM 6)% maximal voluntary contraction (MVC) x min) compared with the Placebo (332 (SEM 69)%MVC x min) (P=0·01) treatments. In contrast, the total AUC for energy expenditure (EE) was approximately 10% higher in the Green tea (23·5 (SEM 1·4) kJ/kg x 180 min) compared with the Placebo (327 (SEM 74) kJ/kg 180 min) (P=0·007) treatments. The decrease in shivering activity combined with an increase in EE, following the ingestion of EGCG and caffeine during the cold exposure, indicates that NST pathways can be significantly stimulated in adult human subjects. The present study provides an experimental approach for human investigations into the potential role of diet and bioactive food ingredients in modulating NST during cold exposure. Stimulating NST pathways in such a manner may also provide important targets in the search of targets for the management of obesity and diabetes.

Brown adipose tissue (BAT) is vital for proper thermogenesis during cold exposure in rodents, but until recently its presence in adult humans and its contribution to human metabolism were thought to be minimal or insignificant. Recent studies using PET with 18F-fluorodeoxyglucose (18FDG) have shown the presence of BAT in adult humans. However, whether BAT contributes to cold-induced nonshivering thermogenesis in humans has not been proven. Using PET with 11C-acetate, 18FDG, and 18F-fluoro-thiaheptadecanoic acid (18FTHA), a fatty acid tracer, we have quantified BAT oxidative metabolism and glucose and nonesterified fatty acid (NEFA) turnover in 6 healthy men under controlled cold exposure conditions. All subjects displayed substantial NEFA and glucose uptake upon cold exposure. Furthermore, we demonstrated cold-induced activation of oxidative metabolism in BAT, but not in adjoining skeletal muscles and subcutaneous adipose tissue. This activation was associated with an increase in total energy expenditure. We found an inverse relationship between BAT activity and shivering. We also observed an increase in BAT radio density upon cold exposure, indicating reduced BAT triglyceride content. In sum, our study provides evidence that BAT acts as a nonshivering thermogenesis effector in humans.

Differences in core temperature and body heat content, generally observed between the luteal and follicular phase of the menstrual cycle, have been reported to modulate the thermogenic activity of cold-exposed women. However, it is unclear how this change in whole body shivering activity will influence fuel selection. The goal of this study was to quantify the effects of the menstrual cycle on muscle recruitment and oxidative fuel selection during low-intensity shivering. Electromyographic activity of eight large muscles was monitored while carbohydrate, lipid, and protein utilization was simultaneously quantified in the follicular and luteal phases of the menstrual cycle in nonacclimatized women shivering at a low intensity. The onset (∼25 min), intensity (∼15% of maximal voluntary contraction), and pattern (∼6 shivering bursts/min) of the shivering response did not differ between menstrual cycle phases, regardless of differences in core temperature and hormone levels. This resulted in lipids remaining the predominant substrate, contributing 75% of total heat production, independent of menstrual phase. We conclude that hormone fluctuations inherent in the menstrual cycle do not affect mechanisms of substrate utilization in the cold. Whether the large contribution of lipids to total heat production in fuel selection confers a survival advantage remains to be established.

This review examines the heat production component of thermoregulation in adult humans. It describes the energy requirements of shivering muscles as they attempt to provide sufficient heat to counterbalance increases in heat loss in cold environments. Emphasis is placed on types of metabolic substrates used under various shivering conditions as well as on the effects energy deficit and food consumption. During shivering, muscle recruitment intensity and pattern of fiber recruitment are highly variable between muscles and individuals. In addition, a number of studies have indicated that shivering can be sustained with different fuels for several hours under variable conditions of cold stress and CHO availability. However, little is still known on the effects of prolonged fasting and energy deficit in the cold on energy metabolism. Even though it is clear that food consumption increases the odds for survival, the metabolic fate of ingested substrates remains highly uncertain. Combining fundamental principles surrounding metabolic fuel selection with applied knowledge of human performance in the cold may allow important breakthroughs in this field of research.

Heat exchange has been thoroughly studied in cold-exposed humans, but the metabolic substrates used for thermogenesis have received less attention. This review deals with oxidative fuel selection in shivering humans. Lipids provide most of the heat during low-intensity shivering, whereas carbohydrates become dominant under more extreme cold conditions. The contribution from plasma glucose always remains minor, but muscle glycogen plays an important role during intense shivering. Whether the size of muscle glycogen stores influences endurance in the cold remains to be demonstrated. The fuel selection patterns of shivering and exercise are different, but the mechanisms underlying this difference have not been investigated. The simultaneous measurement of metabolic substrate oxidation and muscle fibre recruitment has allowed to characterize two different mechanisms of fuel selection in shivering humans: the recruitment of different pathways within the same fibres and of different fuel-specific fibres within the same muscles. This suggests that muscle fibre composition of each individual may affect survival. Future research promises to provide a combination of theoretical advances on fundamental principles of fuel selection and applied strategies to manipulate fibre composition (through training) or fuel metabolism (through diet) to prolong human survival in cold environments.

The thermogenic response of humans depends critically on the coordination of muscle fibre recruitment and oxidative fuel metabolism. The primary goal of this study was to determine whether the electromyographic (EMG) pattern of muscle recruitment could provide metabolic information on oxidative fuel selection during high-intensity shivering. EMG activity (of 8 large muscles) and fuel metabolism were monitored simultaneously in non-acclimatized adult men during high-intensity shivering. Even though acute cold exposure elicited similar changes in metabolic rate among subjects, lipid and carbohydrate use was very different. Depending on the subject, the cold-induced increase in carbohydrate (CHO) oxidation ranged between 2- and 8-fold, with CHO accounting for 33-78% of total heat production, and lipids for 14-60%. This high variability in fuel selection was primarily explained by differences in 'burst shivering' rate, indicating that the recruitment of type II fibres plays a key role in orchestrating fuel selection. This study is the first to show that the pattern of muscle recruitment can provide quantitative information on energy metabolism. Future work should focus on the study of shivering bursts that may provide essential clues on what limits human survival in the cold.