|Year : 2016 | Volume
| Issue : 1 | Page : 3-13
Fluctuation in ambient temperature: interplay between brown adipose tissue, metabolic health, and cardiovascular diseases
Tse-Yao Wang1, Hua Zhou2, Qinghua Sun3
1 Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, Ohio, USA
2 State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, China
3 Division of Environmental Health Sciences, College of Public Health, The Ohio State University; Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio, USA
|Date of Web Publication||14-Apr-2016|
Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, Ohio
Source of Support: None, Conflict of Interest: None
The variations in ambient temperature have been associated with high occurrence of cardiovascular diseases, which is one of the leading global risks for the mortality accounting for 50% of the death in the developed countries. Both heat- and cold-related excess mortalities are mostly attributable to the increase in cardiovascular diseases. Due to the loss of climate system balance caused by increased atmospheric concentration of greenhouse gases, the average global temperatures are expected to rise by 1.1–6.4°C from 1990 to the end of the 21st century. The reinforced intensity, duration, and frequency of heat waves were observed in the past decade with increased average atmosphere and ocean temperature on the Earth. The positive relationship between the heat wave and cardiovascular mortality and morbidity has been demonstrated in the areas with either lower or higher average temperatures. That is, to say, the sudden extreme heat condition lays stress on the cardiovascular system in humans. With a growing body of epidemiological studies, extreme temperature environments and cardiovascular conditions have been increasingly associated. As a class of chronic disorders, the initiation and development of cardiovascular diseases were mainly attributed to metabolic disorders reflecting the prolong stress from obesity, hypertension, hyperglycemia, and hypercholesterolemia whereas the stimulus of sudden temperature change was thought to trigger the onset or worsening of major cardiovascular diseases, which were established by these cumulative risk factors. However, the cold temperature exposure has recently been regarded as a novel therapeutic approach to defense against cardiovascular diseases such as obesity which is resulted from the imbalance between energy intake and energy expenditure. With the chronic mild reduction of ambient temperature, the prevalence and activity of brown adipose tissue (BAT) were upregulated, and the BAT-mediated thermogenesis helps the individual to correct the deviation of energy balance from excess white adipose tissue accumulations. The aim of the present paper was to systematically review the positive and negative effects of the ambient temperature change on cardiovascular diseases, which may lead to new intervention to metabolic health and cardiovascular disease prevention.
Keywords: Cardiovascular diseases, fluctuation in ambient temperature, metabolic health
|How to cite this article:|
Wang TY, Zhou H, Sun Q. Fluctuation in ambient temperature: interplay between brown adipose tissue, metabolic health, and cardiovascular diseases. Environ Dis 2016;1:3-13
|How to cite this URL:|
Wang TY, Zhou H, Sun Q. Fluctuation in ambient temperature: interplay between brown adipose tissue, metabolic health, and cardiovascular diseases. Environ Dis [serial online] 2016 [cited 2022 May 20];1:3-13. Available from: http://www.environmentmed.org/text.asp?2016/1/1/3/180334
| Heat Waves and Cardiovascular Diseases|| |
The cardiovascular system involves body temperature regulations by the redistribution of blood flow. When the body temperature rises, cardiovascular system promotes warm blood circulation to the dilated skin vessels and thereby increases the radiation of body heat to the environment. Under extreme hot condition, most of the output that flows from the heart passes through the skin. When body temperature drops, the constricted superficial capillaries limit the blood flow to the skin. Under extreme cold, the vital organs are protected by the extra blood pumped from the heart. To prevent hypo- and hyper-thermia, the complete and healthy cardiovascular system is essential to perform the task requested by autonomic nervous system (ANS). The development of arterial hardness and thickness, as well as endothelial dysfunction, the key features of cardiovascular diseases, is in a slow and complex progress. However, ambient temperature changes may deteriorate vascular injury and therefore accelerate pathogenesis.,,,
Growing epidemiological researches about ambient temperature changes, either increase or decrease, and adverse health effects have been reported since the late 1940s. The effects of global warming driven by increased emission of greenhouse gas and the burst of human population growth since the late 20th century have led to a higher occurrence of heat wave, a period of abnormally hot weather. With the unchecked current rate of greenhouse gas emission, heat waves would cause excess deaths that would climb from around 700 to range between 3000 and 5000 per year by 2050 in the US. The associations between heat waves and mortality have been extensively reported in Europe and North America. Among the heat waves that have occurred in the recent 20 years in the US, the heat wave in July 1995 in Chicago resulted in approximately 750 heat-related deaths. The results from Semenza et al. revealed that the susceptible individuals with chronic cardiovascular diseases lacked the appropriate cardiac compensatory capacity to become acclimated to heat stress. On the other hand, Kaiser et al. emphasized, inter alia, that during the week of July 14, 1995, through July 20, 1995, 443 deaths of excessive heat were reported with an underlying cardiovascular cause. Between June and August 2003, over 70,000 excess deaths were reported across Europe due to record-breaking high temperatures. Austria, Portugal, Spain, Italy, England, Germany, and Switzerland sustained severe heat waves which resulted in an abrupt increase in heat-related mortality.,,,,,,,,,,,,,, Based on three studies from independent groups, cardiovascular diseases were confirmed to contribute the overall excess mortality during the 2003 European heat wave.,, In addition to Europe and North America, the increased cardiovascular morbidity and mortality were also observed in Asian cities during their heat waves.,,, The relationship between extreme heat and hospital admissions for cardiovascular diseases is less clear. Although most epidemiological studies in either short-,,,, or long-term exposure , indicate increased admission rates for cardiovascular diseases by heat wave, no significant increase in morbidity for cardiovascular diseases during the extreme high temperature was detected by two long-term exposure researches that collected the epidemiological data of a 7-year or 12-year period, respectively., However, the higher mortality rate in cardiovascular diseases indicated by both of these two studies may explain the unparalleled increases in hospital admission. The hypothesis that extreme heat triggers rapid occurrence of cardiovascular diseases that may lead to deaths of patients before they get medical attention has been proposed by Mastrangelo et al. The study on rice harvesters exposed to excessive workplace heat may provide a connection between high ambient temperature and cardiovascular dysfunction. When comparing the peak heart rate of the subjects under three different ambient temperatures, 28–30°C, 31–33.5°C, and 35–36°C, significantly higher peak heart rates were observed in the latter two groups. Besides, the subjects from the lower temperature group had faster heart rate recovery than the higher temperature group after cessation of work. Even though the heat stress resulted from heat exposure has been concluded in the study above, the impact of heat waves on specific groups of people, such as the elderly ,,,,,, and the people with heart disease history, remained unclear. In the last two decades, increasing frequency of heat waves as an effect of worse global warming resulting in elevated mortality and morbidity of cardiovascular diseases has been demonstrated by an expanding body of investigations. Herein, [Table 1] and [Table 2] list selected investigations of heat waves on cardiovascular diseases in terms of morbidity and mortality in humans, respectively.
| Cold Exposure and Cardiovascular Diseases|| |
Climate and weather factors, such as snow, rain, high wind, and low temperature, may cause hypothermia, a condition in which the individuals experience subnormal body temperature and are unable to maintain normal metabolism and body functions. To prevent the onset of hypothermia, maintaining the core body temperature above 35.0°C (95.0 F) is required. Children, the elderly, and the subjects with certain cardiovascular diseases are at higher risk for hypothermia. Since most deaths in hypothermia are caused by cardiovascular dysfunction, the effects and mechanisms of ambient cold stress on cardiovascular system are of increasing interest. To prevent the dissipation of body heat to ambient cold environment, warm-blooded animals including humans reduce circulation of blood in the peripheral blood vessels. As water flows through a pipe by fixed pressure, volumetric flow rate of blood passing through a vessel driven by constant heart pumping is directly proportional to cross-sectional vessel area. Therefore, peripheral vasoconstriction cuts down the amount of blood flow to the skin and reduces the heat release to the environment under the cold stress. The skin surface cooling burdens, such as increasing in left ventricular preload, blood pressure, and myocardial oxygen demand on cardiovascular system, may lead to the incidence of sudden cardiac arrest and cardiac death, especially in the elderly group.,,,,,,,, Both short- and long-term meteorological changes in temperature drops are in association with cardiovascular disorders., In short-term temperature reduction, temperature deviated from the average either in winter or in summer is associated with the incidence of cardiovascular events. From the studies related to cold exposure on cardiovascular dysfunction, a 1°C reduction in daily mean temperature was associated with 2.0% and 1.35% increases in myocardial infarction morbidity and cardiovascular mortality, respectively.,,,, The prevalence of cardiovascular diseases in winter and cold regions has been described since 1960.,,, During the winter, heavy snowfall, cold temperature, and low atmospheric pressure lead to hypertension, a contributing factor to cardiovascular complications and higher cardiovascular mortality. Constantly elevated blood pressure in response to cold stress has been identified to contribute to the development of hypertension in rodent models.,,,,, On the other hand, cold stress not only triggers hypertension commencement but also exacerbates the prevalence of hypertension epidemiologically., During the development of hypertension, related comorbidities such as endothelial dysfunction, left ventricular hypertrophy, and accelerated atherosclerotic process contribute to coronary heart disease and cerebrovascular disease (stroke). Thus, the effects of cold spell on cardiovascular mortality in humans are summarized in [Table 3].
There is no doubt that capabilities of heart and vascular system are gradually declining with age, and the aging process is associated with loss of vascular compliance, disorder of vessel resistance, and increased activity of sympathetic nervous system (SNS). The structural changes in the arteries of aged individuals are responsible for the loss of arterial compliance. With age-associated increases in arterial stiffness, the pressor response is further augmented by cold stress in the elderly. In addition to the loss of arterial compliance, resistance vessel vasodilatation and vasoconstriction play a central and pathophysiological role in cerebrovascular resistance  and are affected by aging via two homeostatic systems namely L-arginine-NO system and catecholamine α1-adrenergic receptor (AR) system. However, the relationship between age-related decrease in resistance vessel responsiveness and cold stress has yet to be characterized. As a critical component of ANS, SNS is involved in both thermal and cardiovascular homeostasis. The age-related increase in rest SNS activity resulted from the augmented rate of norepinephrine (NE) release into plasma.,, NE acts as a stress hormone to cause vasoconstriction and increases blood pressure and heart rate under environmental stress. However, chronic age-related NE spillover to plasma is implicated in the pathogenesis of hypertension, which is developed and maintained by cold exposure., Although epidemiological studies refer the elderly to the group of higher morbidity and mortality in cold-induced cardiovascular diseases, further investigations on the mechanism of cold stress to cardiovascular dysfunction in elderly remain needed.
| Cardiovascular Benefits from Cold Exposure|| |
Metabolic disorders and cardiovascular diseases
Cardiovascular disease is a very prevalent chronic condition and is the leading cause of death globally. Two major categories of cardiovascular risk factors have been proposed as modifiable and nonmodifiable risk factors. The risk factors that cannot be changed such as age, gender, race/ethnicity, and family history are so-called nonmodifiable risk factors; however, nevertheless, being aware of and receiving regular checkups for these risk factors can help the prevention of cardiovascular diseases. Managing the modifiable risk factors is critical for preventing, treating, and controlling cardiovascular disease. As we look over the modifiable cardiovascular risk factors including the use of alcohol and tobacco, unhealthy diet, physical inactivity, high cholesterol and lipids, obesity, diabetes, and hypertension, the reciprocal relationship between these risk factors and energy homeostasis has been unmasked. The energy homeostasis can be illustrated by a simple formula: Energy intake = energy expenditure + energy storage. To perfectly keep the energy homeostasis in a balanced status, energy expenditure must meet energy intake. However, unhealthy diet and physical inactivity increase the energy intake and decrease the energy expenditure, respectively, which ultimately leads to high circulating cholesterol levels and obesity, the net result of excess energy storage. Obesity is further predisposing to diabetes and hypertension. To avoid obesity and related cardiovascular diseases, appetite suppressants and physical activities have long been applied as therapeutic approaches to the loss of energy balance by excessive energy intake and poor energy expenditure, respectively. However, several anorectics have been withdrawn from the market due to their adverse drug reactions. Achieving and maintaining regular physical activity with enough intensity to keep sufficient metabolic rate for energy expenditure may not be applicable for specific groups that suffer from obesity.
Rediscovery of brown adipose tissue in adult humans
In 1551, interscapular brown adipose tissue (BAT) was first described in mammals including human. Scientists believe that the disappearance of BAT occurred immediately after infancy in humans. The rediscovery of BAT in adult humans under cold environment has shown therapeutic potential for obesity and related cardiovascular diseases mostly due to the imaging advancement of positron emission tomography-computed tomography (PET/CT). In comparison to white adipose tissue (WAT), the major reservoir for energy in the form of triglycerides, BAT functions for whole body energy expenditure via oxidative metabolism in response to environmental and/or physiological stimuli. With the expression of uncoupling protein 1 (UCP1) on the inner membrane of brown adipocyte mitochondria, adenosine triphosphate synthesis is uncoupled from respiratory electron transport chain into the heat for nonshivering thermogenesis in the cold. As exposed to cold environment, glucose uptake of “active” BAT is around ten times more than the “rest” one in human subjects. Besides glucose disposal, cold exposure promotes BAT-mediated triglyceride clearance to correct hyperlipidemia in mouse models., The huge amount intake of glucose in the interscapular BAT was unintentionally detected by regular  F-fluorodeoxyglucose  PET/CT scans for cancer patients with metabolically active tumor cells. These false-positive signals were thought to be emitted from muscle cells rather than adipocytes until a decade ago.,, This uptake in supraclavicular area fat was further confirmed as BAT functionally, physiologically, and genetically.,, The huge capacity of active BAT to shift the balance between calorie intake and expenditure was reported in both animals and humans under the stress from cold exposure; in another word, cold exposure can manage the obesity, which may be a therapeutic target for cardiovascular diseases.
Sympathetic nervous system on brown adipose tissue thermogenesis
Adaptive thermoregulation of BAT in mammals including both hibernators and nonhibernators has been investigated since the 1960s. During cold exposure, NE released from SNS terminals binds to beta 3-AR (β3-AR) on the surface of brown adipocyte, leading to the stimulation of UCP1 via a cascade of signal transductions involving in cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), and cAMP response element binding protein (CREB). Upon NE stimulation, free fatty acids released from lipolysis serve as major substrates for thermogenesis and regulators of UCP1 activity in brown adipocytes. The predominant role of UCP1 in cold-induced thermogenesis is confirmed in UCP1-deficient mouse models.,, Therefore, the existence of UCP1 is iconic for the thermogenic adipose tissues. The synergism between SNS and thyroid hormones is fundamental in adaptive thermogenesis. Thyroid hormones, triiodothyronine (T3) and thyroxin (T4), are mainly produced by follicular cells in the thyroid gland and involve in systemic energy balance and lipid metabolism. Iodothyronine deiodinases activate thyroid function by transferring T4 to a more active form of thyroid hormone, T3, in different tissues such as liver, kidney, heart, skeletal muscle, CNS, adipose tissue, and thyroid. The conversion of T4 to T3 is performed in BAT by a specific member of deiodinase enzyme subfamily, type II iodothyronine deiodinase (DIO2). Since NE infusion was unable to increase BAT thermal production in hypothyroid rats, hypothyroidism caused the subjects to fail to survive cold exposure. The reduced responsiveness to adrenergic stimulation in hypothyroid rats is due to the deviation of adrenergic signaling pathway of BAT.,, At the organ level, the SNS activity is modulated by thyroid hormones via AMP-activated protein kinase (AMPK) activity and lipid metabolism in the ventromedial nuclei of hypothalamus. SNS is lined up between thyroid gland and BAT for energy homeostasis. Increased energy expenditure and weight loss are the features of hyperthyroidism which is caused by overproduction of thyroid hormones (T3 and T4)., However, the molecular mechanism accounting for the deviated energy homeostasis induced by hyperthyroidism had not been clarified until 2010. As López et al. wrote, “here, we demonstrate that either whole body hyperthyroidism or central administration of T3 decreases the activity of hypothalamic AMPK, increases SNS activity, and upregulates thermogenic markers in BAT.” Based on their pioneer work, the cascade of SNS/NE/β3-AR/BAT thermogenesis is upon the upstream endocrine thyroid. However, the importance of cell-autonomous T3 on BAT differentiation, development, and oxidative capacity was emphasized by conditional DIO2 knockout mouse model (D2KO).,,, DIO2 was important for the enzymatic activity to produce bioactive T3 from T4 resulting in thyroid hormone activation of individual brown adipocyte. In the 1980s, DIO2 was reported to be highly expressed in BAT  and the BAT-derived DIO2 was stimulated by SNS. Mice with targeted disruption of DIO2 gene in brown adipocytes are prone to hypothermia under cold stress and are more susceptible to diet-induced obesity due to the impaired embryonic BAT development. The differentiation and development of BAT to exhibit thermogenic proteins including UCP1, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and thermoregulation are achieved by DIO2-generated T3 instead of serum T3. Therefore, cold exposure not only activates UCP1-mediated thermogenesis in an individual brown adipocyte (activity state) to maintain normothermia but also results at higher states in hyperplasia (adipocyte number) and hypertrophy (adipocyte size) of thermogenic adipocytes.
Cold stress and beige adipocyte browning
Besides classic BAT, the emergence of beige adipocytes in WAT predominant depots by prolonged cold stimulation is able to achieve hyperplasia of thermogenic adipose tissues. Beige adipocyte, in contrast to the classic interscapular and perirenal brown adipocytes sharing the same progenitor (Myf5+ lineage) with skeletal muscle, comes from a distinct Myf5+ cell lineage. Different genetic models were investigated to clarify the mechanisms involved in the cold-induced beige adipocytes in terms of their development and function. PGC-1α and PR domain containing 16 (PRDM16) are of particular interest because of their critical roles in promoting the “browning” effect in WAT. Under cold stress, quick and high intensity of PGC-1α activation makes itself a dominant regulator of mitochondrial biogenesis and oxidative metabolism. This extreme cold sensitive coactivator is under the control of NE/β3-AR/cAMP/PKA/CREB pathway to induce the expression of UCP1 and enzymes related to mitochondrial respiratory chain. Even though WAT can be equipped with thermogenic features by transgenic expression of PGC-1α and deficiency of PGC-1α ablates the cold-induced thermogenesis in mouse model, no impacts of PGC-1α loss on normal brown fat differentiation have been detected. PRDM16 is a transcriptional factor essential for brown fat phenotypes via induction of PGC-1α and UCP1 expressions and thereby causes the stimulation of uncoupled respiration in response to β3-adrenergic stimulation. Seale et al. and Liu et al. rightly point out that PRDM16 drives PGC-1α and PGC-1β activations by direct protein–protein interactions leading to the browning of the adipose cells in WAT depots and improving whole-body insulin sensitivity and glucose tolerance., The existence of PRDM16 that gives rise to the brown adipocyte identity and suppresses WAT gene expressions is likely to determine the adipocyte fate. As mentioned above, DIO2 is also an applicable thermogenic marker for browning adipocytes. By monitoring the expression level of these thermogenic genes in vitro and in vivo as well as the NE/β3-AR/BAT thermogenesis pathway, the beige cells were reported to be induced by cold exposure in a cell-autonomous manner in addition to NE/β3-AR/cAMP/PKA/CREB axis. The direct cold temperature stimulated thermogenesis occurs in subcutaneous fat but visceral fat and classic BAT. Although both visceral and subcutaneous fat depots were characterized as white adipocytes and play critical role in energy storage and thermic insulation, subcutaneous fat depot has been discovered with substantial thermogenic capacity induced by cold exposure with or without β-AR stimulation. The unique thermogenic response of subcutaneous fat depots to direct cold stress could be explained by their composition and anatomic location. The analysis of the activation of thermogenic program in various cultured adipocytes including beige, white, and brown cell lines concluded that direct cold exposure-induced thermogenic program is specific to white and beige adipocytes which are relatively predominant in subcutaneous fat. In contrast to another white adipocyte-rich visceral fat depot located deeply in the belly, subcutaneous fat depots certainly sense much more fluctuations in environmental temperatures.
Emergence of beige adipocyte
To explain how beige cells are born by cold acclimatization, different hypotheses have been proposed. White-to-brown transdifferentiation processes in adipocytes and scouting of distinct beige adipocyte lineage are actively investigated among the assumptions. Transdifferentiation is defined as a process of converting a mature cell from one differentiated type to another and therefore can bring about the emergence of browning adipocytes in WAT. β3-adrenergic stimulation driven by cold acclimatization plays an important role in white-to-brown adipocyte transdifferentiation in WAT because there is no occurrence of browning cells upon cold stress in β3-adrenoceptor knockout mice; whereas the administration of β3-adrenoceptor agonist promotes the browning phenotypes in normal mice. On the other hand, the plasticity of subcutaneous fat is also explained by the complex in their constituent parts. Under ambient temperature, a specific type of multilocular brown-fat-like cells residing in subcutaneous fat of 129SVE mice was detected without any cold acclimatization. These brown-fat-like cells exhibit intermediate phenotype of thermogenic gene expressions between white and classic brown adipocytes. This beige adipocyte possesses the characteristics of both white and brown adipocytes regarding function and molecular properties. However, the features toward classic BAT thermogenesis are significantly induced upon cAMP stimulation. The de novo adipogenesis from the precursor cell to beige adipocyte in subcutaneous fat depot was further proved by AdipoChaser mouse developed by Wang et al. The prevalent of beige cells either from white-to-brown transdifferentiation or distinct subgroup of precursor cells provides high physiological plasticity of WAT in subcutaneous fat, which is definitely a target for metabolic defects.
Modalities to nonshivering thermogenesis
Due to the fundamental role of NE/β3-AR/cAMP/PKA/CREB axis in cold-induced thermogenesis, sympathomimetic drugs have been thought of potential remedies for metabolic complications. However, systemic application of β-agonist isoprenaline does not activate BAT in humans even though the energy expenditure is elevated to the same extent as exposed to cold stress. In addition, ephedrine, a classic agonist of NE at ARs, fails to induce BAT thermogenesis in humans. Since β-adrenergic compounds are inadequate to therapeutic needs in metabolic disorders, the modalities other than pharmacological agents have been proposed. Exercise,, electrical stimulation, and cold exposure have gained interest as physical stimuli to active BAT thermogenesis. The benefits of exercise on skeletal muscle in BAT thermogenesis come from PGC-1α-mediated irisin production. Irisin is a hormone cleaved and secreted from membrane FNDC5 protein in the skeletal muscle. Both exercise training and overexpression of PGC-1α induce irisin production leading to the browning of white adipocytes and improved systemic metabolism in mouse model. However, according to human genomic DNA analysis and unchanged FNDC5 mRNA expression in response to exercise in human subjects, the beneficial effect of irisin observed in mice is unlikely translated to clinical application. Establishing electrical field to stimulate NE released from sympathetic nerves is proved to induce BAT thermogenesis, but intensive investigations for this novel physical modality on BAT thermogenesis are rarely described. Cold as a stimulus to induce nonshivering thermogenesis was observed in rodents in the 1950s,,, and BAT was believed to be the main site of nonshivering thermogenesis by cold from the 1960s based on the discoveries of Smith et al.,,, The initial experiments to induce nonshivering thermogenesis were mostly performed under harsh conditions of high intensity of cold stress (~4°C) and prolonged cold exposure (>2 weeks) in rodents. However, short-term (<24 h) of 4°C cold exposure is able to alter lipoprotein profile  and mild cold exposure is sufficient to induce UCP1-mediated BAT activation in both rodent models and human subjects.,, Thermal neutral zone, a range of ambient temperatures to minimize the loss of metabolic body heat production to the external environment, is widely accepted at 25–27°C of ambient temperature to naked adults, mild cold exposures ranged from 14 to 19°C immediately increase UCP1 expression, BAT thermogenesis, and related metabolic benefit in humans.,,,,,,,, Compared to the cold exposure for a short period but in high intensity, mild and prolonged cold exposure leading to BAT thermogenesis provide a practicable basis for treatment of obesity and metabolic diseases. It is evident from recent studies that a mild reduction of ambient temperature (19°C) is able to increase human BAT activity and corresponding lipolysis and energy expenditure., The population increased in obesity, which are paralleled to gradual increased thermal exposures of indoor temperatures, could be taken as presumptive evidence of the effects of mild cold exposure in BAT thermogenesis and energy expenditure.
| Conclusion|| |
This review examined the fluctuations in ambient temperature to cardiovascular diseases and the benefit effects of mild reduction of ambient temperature in terms of energy expenditure and obesity and related complications [Figure 1]. It is evident from epidemiologic studies that there is an increase of impacts on morbidity and mortality of cardiovascular diseases during extreme weather in western countries in the recent decades. As a result, newly established evaluation criteria might help ensure effective and efficient weather warning system. In Asian regions, both short- and long-term researches examining the impact of extreme temperatures on morbidity and mortality have been launched recently. However, these studies were only in small scales and focused on limited cities in Korea and China.,,,,,,,,,,,,,,, Therefore, future studies to better define and classify etiologies contributing to extreme ambient temperature-related morbidity and mortality in Asian areas are needed and would be helpful in planning preventive strategies for vulnerable populations such as children, the elderly, and the subjects with cardiovascular diseases.
|Figure 1: Schematic summary illustrating ambient temperature changes on human health and disease development via adipose tissues. “Brown” means brown adipose tissue while “white” means white adipose tissue. “+” represents promotion/increase while “–” represents inhibition/decrease|
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The association of obesity with the development and deterioration of cardiovascular diseases, which lead to the vulnerability during the extreme weather events, has been widely investigated, and different therapeutic targeting obesity-mediated heart diseases have been proposed. The mechanisms of BAT thermogenesis in energy homeostasis have made great strides in the recent years with a growing body of in vitro and in vivo studies, which suggests mild cold exposure as a potential physical modality against obesity and related heart complications. However, although the latest findings support mild reduction of environmental temperature for reducing obesity, metabolic syndrome, and cardiovascular disease via BAT thermogenesis, the optimization of mild cold intervention might need to be achieved by further clinical trials.
Financial support and sponsorship
This work was supported by NIH grant ES018900 to Dr. Sun.
Conflicts of interest
There are no conflicts of interest.
| References|| |
Hess KL, Wilson TE, Sauder CL, Gao Z, Ray CA, Monahan KD. Aging affects the cardiovascular responses to cold stress in humans. J Appl Physiol (1985) 2009;107:1076-82.
Chorro FJ, Guerrero J, Ferrero A, Tormos A, Mainar L, Millet J, et al.
Effects of acute reduction of temperature on ventricular fibrillation activation patterns. Am J Physiol Heart Circ Physiol 2002;283:H2331-40.
Edwards DG, Gauthier AL, Hayman MA, Lang JT, Kenefick RW. Acute effects of cold exposure on central aortic wave reflection. J Appl Physiol (1985) 2006;100:1210-4.
Ganio MS, Brothers RM, Shibata S, Hastings JL, Crandall CG. Effect of passive heat stress on arterial stiffness. Exp Physiol 2011;96:919-26.
Semenza JC, McCullough JE, Flanders WD, McGeehin MA, Lumpkin JR. Excess hospital admissions during the July 1995 heat wave in Chicago. Am J Prev Med 1999;16:269-77.
Kaiser R, Le Tertre A, Schwartz J, Gotway CA, Daley WR, Rubin CH. The effect of the 1995 heat wave in Chicago on all-cause and cause-specific mortality. Am J Public Health 2007;97 Suppl 1:S158-62.
Robine JM, Cheung SL, Le Roy S, Van Oyen H, Griffiths C, Michel JP, et al.
Death toll exceeded 70,000 in Europe during the summer of 2003. C R Biol 2008;331:171-8.
Hutter HP, Moshammer H, Wallner P, Leitner B, Kundi M. Heatwaves in Vienna: Effects on mortality. Wien Klin Wochenschr 2007;119:223-7.
Muthers S, Matzarakis A, Koch E. Summer climate and mortality in Vienna – A human-biometeorological approach of heat-related mortality during the heat waves in 2003. Wien Klin Wochenschr 2010;122:525-31.
Nogueira PJ, Falcão JM, Contreiras MT, Paixão E, Brandão J, Batista I. Mortality in Portugal associated with the heat wave of August 2003: Early estimation of effect, using a rapid method. Euro Surveill 2005;10:150-3.
Simón F, Lopez-Abente G, Ballester E, Martínez F. Mortality in Spain during the heat waves of summer 2003. Euro Surveill 2005;10:156-61.
Montero JC, Mirón IJ, Criado-Álvarez JJ, Linares C, Díaz J. Influence of local factors in the relationship between mortality and heat waves: Castile-La Mancha (1975-2003). Sci Total Environ 2012;414:73-80.
Centers for Disease Control and Prevention (CDC). Impact of heat waves on mortality – Rome, Italy, June-August 2003. MMWR Morb Mortal Wkly Rep 2004;53:369-71.
Michelozzi P, de Donato F, Bisanti L, Russo A, Cadum E, DeMaria M, et al.
The impact of the summer 2003 heat waves on mortality in four Italian cities. Euro Surveill 2005;10:161-5.
Conti S, Meli P, Minelli G, Solimini R, Toccaceli V, Vichi M, et al.
Epidemiologic study of mortality during the summer 2003 heat wave in Italy. Environ Res 2005;98:390-9.
Stafoggia M, Forastiere F, Agostini D, Biggeri A, Bisanti L, Cadum E, et al.
Vulnerability to heat-related mortality: A multicity, population-based, case-crossover analysis. Epidemiology 2006;17:315-23.
Conti S, Masocco M, Meli P, Minelli G, Palummeri E, Solimini R, et al.
General and specific mortality among the elderly during the 2003 heat wave in Genoa (Italy). Environ Res 2007;103:267-74.
Johnson H, Kovats RS, McGregor G, Stedman J, Gibbs M, Walton H, et al.
The impact of the 2003 heat wave on mortality and hospital admissions in England. Health Stat Q 2005;25:6-11.
Johnson H, Kovats RS, McGregor G, Stedman J, Gibbs M, Walton H. The impact of the 2003 heat wave on daily mortality in England and Wales and the use of rapid weekly mortality estimates. Euro Surveill 2005;10:168-71.
Hertel S, Le Tertre A, Jöckel KH, Hoffmann B. Quantification of the heat wave effect on cause-specific mortality in Essen, Germany. Eur J Epidemiol 2009;24:407-14.
Grize L, Huss A, Thommen O, Schindler C, Braun-Fahrländer C. Heat wave 2003 and mortality in Switzerland. Swiss Med Wkly 2005;135:200-5.
Cerutti B, Tereanu C, Domenighetti G, Cantoni E, Gaia M, Bolgiani I, et al.
Temperature related mortality and ambulance service interventions during the heat waves of 2003 in Ticino (Switzerland). Soz Praventivmed 2006;51:185-93.
Rey G, Jougla E, Fouillet A, Pavillon G, Bessemoulin P, Frayssinet P, et al.
The impact of major heat waves on all-cause and cause-specific mortality in France from 1971 to 2003. Int Arch Occup Environ Health 2007;80:615-26.
Huang W, Kan H, Kovats S. The impact of the 2003 heat wave on mortality in Shanghai, China. Sci Total Environ 2010;408:2418-20.
Ma W, Xu X, Peng L, Kan H. Impact of extreme temperature on hospital admission in Shanghai, China. Sci Total Environ 2011;409:3634-7.
Son JY, Lee JT, Anderson GB, Bell ML. The impact of heat waves on mortality in seven major cities in Korea. Environ Health Perspect 2012;120:566-71.
Yang J, Liu HZ, Ou CQ, Lin GZ, Ding Y, Zhou Q, et al.
Impact of heat wave in 2005 on mortality in Guangzhou, China. Biomed Environ Sci 2013;26:647-54.
Khalaj B, Lloyd G, Sheppeard V, Dear K. The health impacts of heat waves in five regions of New South Wales, Australia: A case-only analysis. Int Arch Occup Environ Health 2010;83:833-42.
Basu R, Pearson D, Malig B, Broadwin R, Green R. The effect of high ambient temperature on emergency room visits. Epidemiology 2012;23:813-20.
Lin S, Luo M, Walker RJ, Liu X, Hwang SA, Chinery R. Extreme high temperatures and hospital admissions for respiratory and cardiovascular diseases. Epidemiology 2009;20:738-46.
Kovats RS, Hajat S, Wilkinson P. Contrasting patterns of mortality and hospital admissions during hot weather and heat waves in Greater London, UK. Occup Environ Med 2004;61:893-8.
Michelozzi P, Accetta G, De Sario M, D'Ippoliti D, Marino C, Baccini M, et al.
High temperature and hospitalizations for cardiovascular and respiratory causes in 12 European cities. Am J Respir Crit Care Med 2009;179:383-9.
Mastrangelo G, Hajat S, Fadda E, Buja A, Fedeli U, Spolaore P. Contrasting patterns of hospital admissions and mortality during heat waves: Are deaths from circulatory disease a real excess or an artifact? Med Hypotheses 2006;66:1025-8.
Sahu S, Sett M, Kjellstrom T. Heat exposure, cardiovascular stress and work productivity in rice harvesters in India: Implications for a climate change future. Ind Health 2013;51:424-31.
Huynen MM, Martens P, Schram D, Weijenberg MP, Kunst AE. The impact of heat waves and cold spells on mortality rates in the Dutch population. Environ Health Perspect 2001;109:463-70.
Wang XY, Barnett AG, Yu W, FitzGerald G, Tippett V, Aitken P, et al.
The impact of heatwaves on mortality and emergency hospital admissions from non-external causes in Brisbane, Australia. Occup Environ Med 2012;69:163-9.
Knowlton K, Rotkin-Ellman M, King G, Margolis HG, Smith D, Solomon G, et al.
The 2006 California heat wave: Impacts on hospitalizations and emergency department visits. Environ Health Perspect 2009;117:61-7.
Ostro B, Rauch S, Green R, Malig B, Basu R. The effects of temperature and use of air conditioning on hospitalizations. Am J Epidemiol 2010;172:1053-61.
Braga AL, Zanobetti A, Schwartz J. The effect of weather on respiratory and cardiovascular deaths in 12 U.S. cities. Environ Health Perspect 2002;110:859-63.
Vaneckova P, Bambrick H. Cause-specific hospital admissions on hot days in Sydney, Australia. PLoS One 2013;8:e55459.
Barnett AG, Hajat S, Gasparrini A, Rocklöv J. Cold and heat waves in the United States. Environ Res 2012;112:218-24.
Revich B, Shaposhnikov D. Excess mortality during heat waves and cold spells in Moscow, Russia. Occup Environ Med 2008;65:691-6.
Rocklöv J, Forsberg B. The effect of temperature on mortality in Stockholm 1998-2003: A study of lag structures and heatwave effects. Scand J Public Health 2008;36:516-23.
Hong YC, Rha JH, Lee JT, Ha EH, Kwon HJ, Kim H. Ischemic stroke associated with decrease in temperature. Epidemiology 2003;14:473-8.
Raguz M, Bergovec M, Kranjcec D, Vrazic H, Puksic S. A cold shock response triggering acute myocardial infarction. Int J Cardiol 2008;128:e37-9.
Wilson TE, Tollund C, Yoshiga CC, Dawson EA, Nissen P, Secher NH, et al.
Effects of heat and cold stress on central vascular pressure relationships during orthostasis in humans. J Physiol 2007;585(Pt 1):279-85.
Wilson TE, Gao Z, Hess KL, Monahan KD. Effect of aging on cardiac function during cold stress in humans. Am J Physiol Regul Integr Comp Physiol 2010;298:R1627-33.
Ma W, Yang C, Chu C, Li T, Tan J, Kan H. The impact of the 2008 cold spell on mortality in Shanghai, China. Int J Biometeorol 2013;57:179-84.
de'Donato FK, Leone M, Noce D, Davoli M, Michelozzi P. The impact of the February 2012 cold spell on health in Italy using surveillance data. PLoS One 2013;8:e61720.
Xie H, Yao Z, Zhang Y, Xu Y, Xu X, Liu T, et al.
Short-term effects of the 2008 cold spell on mortality in three subtropical cities in Guangdong Province, China. Environ Health Perspect 2013;121:210-6.
Ha J, Yoon J, Kim H. Relationship between winter temperature and mortality in Seoul, South Korea, from 1994 to 2006. Sci Total Environ 2009;407:2158-64.
Korhonen I. Blood pressure and heart rate responses in men exposed to arm and leg cold pressor tests and whole-body cold exposure. Int J Circumpolar Health 2006;65:178-84.
Kysely J, Pokorna L, Kyncl J, Kriz B. Excess cardiovascular mortality associated with cold spells in the Czech Republic. BMC Public Health 2009;9:19.
Wolf K, Schneider A, Breitner S, von Klot S, Meisinger C, Cyrys J, et al.
Air temperature and the occurrence of myocardial infarction in Augsburg, Germany. Circulation 2009;120:735-42.
Yang TC, Wu PC, Chen VY, Su HJ. Cold surge: A sudden and spatially varying threat to health? Sci Total Environ 2009;407:3421-4.
Bhaskaran K, Hajat S, Haines A, Herrett E, Wilkinson P, Smeeth L. Short term effects of temperature on risk of myocardial infarction in England and Wales: Time series regression analysis of the myocardial ischaemia national audit project (MINAP) registry. BMJ 2010;341:c3823.
Analitis A, Katsouyanni K, Biggeri A, Baccini M, Forsberg B, Bisanti L, et al.
Effects of cold weather on mortality: Results from 15 European cities within the PHEWE project. Am J Epidemiol 2008;168:1397-408.
Töro K, Bartholy J, Pongrácz R, Kis Z, Keller E, Dunay G. Evaluation of meteorological factors on sudden cardiovascular death. J Forensic Leg Med 2010;17:236-42.
Madrigano J, Mittleman MA, Baccarelli A, Goldberg R, Melly S, von Klot S, et al.
Temperature, myocardial infarction, and mortality: Effect modification by individual- and area-level characteristics. Epidemiology 2013;24:439-46.
Smith RE, Hock RJ. Brown fat: Thermogenic effector of arousal in hibernators. Science 1963;140:199-200.
Smith RE, Roberts JC. Thermogenesis of brown adipose tissue in cold-acclimated rats. Am J Physiol 1964;206:143-8.
Dawkins MJ, Hull D. Brown adipose tissue and the response of new-born rabbits to cold. J Physiol 1964;172:216-38.
Thom TJ, Epstein FH. Heart disease, cancer, and stroke mortality trends and their interrelations. An international perspective. Circulation 1994;90:574-82.
van Bergen P, Fregly MJ, Rossi F, Shechtman O. The effect of intermittent exposure to cold on the development of hypertension in the rat. Am J Hypertens 1992;5:548-55.
Shechtman O, Fregly MJ, Papanek PE. Factors affecting cold-induced hypertension in rats. Proc Soc Exp Biol Med 1990;195:364-8.
Fregly MJ, Kikta DC, Threatte RM, Torres JL, Barney CC. Development of hypertension in rats during chronic exposure to cold. J Appl Physiol (1985) 1989;66:741-9.
Fregly MJ, Rossi F, Sun Z, Tümer N, Cade JR, Hegland D, et al.
Effect of chronic treatment with prazosin and L-arginine on the elevation of blood pressure during cold exposure. Pharmacology 1994;49:351-62.
Sun Z, Cade R, Katovich MJ, Fregly MJ. Body fluid distribution in rats with cold-induced hypertension. Physiol Behav 1999;65:879-84.
Roukoyatkina NI, Chefer SI, Rifkind J, Ajmani R, Talan MI. Cold acclimation-induced increase of systolic blood pressure in rats is associated with volume expansion. Am J Hypertens 1999;12(1 Pt 1):54-62.
Lejeune JP, Vinchon M, Amouyel P, Escartin T, Escartin D, Christiaens JL. Association of occurrence of aneurysmal bleeding with meteorologic variations in the north of France. Stroke 1994;25:338-41.
Minami J, Kawano Y, Ishimitsu T, Yoshimi H, Takishita S. Seasonal variations in office, home and 24 h ambulatory blood pressure in patients with essential hypertension. J Hypertens 1996;14:1421-5.
Schmoker JD, Terrien C 3rd
, McPartland KJ, Boyum J, Wellman GC, Trombley L, et al.
Cerebrovascular response to continuous cold perfusion and hypothermic circulatory arrest. J Thorac Cardiovasc Surg 2009;137:459-64.
Lake CR, Ziegler MG, Coleman MD, Kopin IJ. Age-adjusted plasma norepinephrine levels are similar in normotensive and hypertensive subjects. N Engl J Med 1977;296:208-9.
Rubin PC, Scott PJ, McLean K, Reid JL. Noradrenaline release and clearance in relation to age and blood pressure in man. Eur J Clin Invest 1982;12:121-5.
Goldstein DS, Lake CR, Chernow B, Ziegler MG, Coleman MD, Taylor AA, et al.
Age-dependence of hypertensive-normotensive differences in plasma norepinephrine. Hypertension 1983;5:100-4.
Kim JY, Jung KY, Hong YS, Kim JI, Jang TW, Kim JM. The relationship between cold exposure and hypertension. J Occup Health 2003;45:300-6.
Klingenberg M. Uncoupling protein – A useful energy dissipator. J Bioenerg Biomembr 1999;31:419-30.
Orava J, Nuutila P, Lidell ME, Oikonen V, Noponen T, Viljanen T, et al.
Different metabolic responses of human brown adipose tissue to activation by cold and insulin. Cell Metab 2011;14:272-9.
Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, Peldschus K, et al.
Brown adipose tissue activity controls triglyceride clearance. Nat Med 2011;17:200-5.
Nedergaard J, Bengtsson T, Cannon B. New powers of brown fat: Fighting the metabolic syndrome. Cell Metab 2011;13:238-40.
Hany TF, Gharehpapagh E, Kamel EM, Buck A, Himms-Hagen J, von Schulthess GK. Brown adipose tissue: A factor to consider in symmetrical tracer uptake in the neck and upper chest region. Eur J Nucl Med Mol Imaging 2002;29:1393-8.
Cohade C, Osman M, Pannu HK, Wahl RL. Uptake in supraclavicular area fat (“USA-Fat”): Description on 18F-FDG PET/CT. J Nucl Med 2003;44:170-6.
Cohade C, Mourtzikos KA, Wahl RL. “USA-Fat”: Prevalence is related to ambient outdoor temperature-evaluation with 18F-FDG PET/CT. J Nucl Med 2003;44:1267-70.
van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, et al.
Cold-activated brown adipose tissue in healthy men. N Engl J Med 2009;360:1500-8.
Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, et al.
Identification and importance of brown adipose tissue in adult humans. N Engl J Med 2009;360:1509-17.
Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, et al.
Functional brown adipose tissue in healthy adults. N Engl J Med 2009;360:1518-25.
Kozak UC, Kopecky J, Teisinger J, Enerbäck S, Boyer B, Kozak LP. An upstream enhancer regulating brown-fat-specific expression of the mitochondrial uncoupling protein gene. Mol Cell Biol 1994;14:59-67.
Enerbäck S, Jacobsson A, Simpson EM, Guerra C, Yamashita H, Harper ME, et al.
Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 1997;387:90-4.
Golozoubova V, Hohtola E, Matthias A, Jacobsson A, Cannon B, Nedergaard J. Only UCP1 can mediate adaptive nonshivering thermogenesis in the cold. FASEB J 2001;15:2048-50.
Leonard JL, Mellen SA, Larsen PR. Thyroxine 5'-deiodinase activity in brown adipose tissue. Endocrinology 1983;112:1153-5.
Ribeiro MO, Lebrun FL, Christoffolete MA, Branco M, Crescenzi A, Carvalho SD, et al.
Evidence of UCP1-independent regulation of norepinephrine-induced thermogenesis in brown fat. Am J Physiol Endocrinol Metab 2000;279:E314-22.
Bauer GC, Lindberg L, Naversten Y, Sjöstrand LO. 85Sr radionuclide scintimetry in infected total hip arthroplasty. Acta Orthop Scand 1973;44:439-50.
Carvalho SD, Bianco AC, Silva JE. Effects of hypothyroidism on brown adipose tissue adenylyl cyclase activity. Endocrinology 1996;137:5519-29.
Rubio A, Raasmaja A, Silva JE. Thyroid hormone and norepinephrine signaling in brown adipose tissue. II: Differential effects of thyroid hormone on beta 3-adrenergic receptors in brown and white adipose tissue. Endocrinology 1995;136:3277-84.
Rubio A, Raasmaja A, Maia AL, Kim KR, Silva JE. Effects of thyroid hormone on norepinephrine signaling in brown adipose tissue. I. Beta 1- and beta 2-adrenergic receptors and cyclic adenosine 3',5'-monophosphate generation. Endocrinology 1995;136:3267-76.
Pijl H, de Meijer PH, Langius J, Coenegracht CI, van den Berk AH, Chandie Shaw PK, et al.
Food choice in hyperthyroidism: Potential influence of the autonomic nervous system and brain serotonin precursor availability. J Clin Endocrinol Metab 2001;86:5848-53.
Herwig A, Ross AW, Nilaweera KN, Morgan PJ, Barrett P. Hypothalamic thyroid hormone in energy balance regulation. Obes Facts 2008;1:71-9.
López M, Varela L, Vázquez MJ, Rodríguez-Cuenca S, González CR, Velagapudi VR, et al.
Hypothalamic AMPK and fatty acid metabolism mediate thyroid regulation of energy balance. Nat Med 2010;16:1001-8.
Castillo M, Hall JA, Correa-Medina M, Ueta C, Kang HW, Cohen DE, et al.
Disruption of thyroid hormone activation in type 2 deiodinase knockout mice causes obesity with glucose intolerance and liver steatosis only at thermoneutrality. Diabetes 2011;60:1082-9.
Marsili A, Aguayo-Mazzucato C, Chen T, Kumar A, Chung M, Lunsford EP, et al.
Mice with a targeted deletion of the type 2 deiodinase are insulin resistant and susceptible to diet induced obesity. PLoS One 2011;6:e20832.
Hall JA, Ribich S, Christoffolete MA, Simovic G, Correa-Medina M, Patti ME, et al.
Absence of thyroid hormone activation during development underlies a permanent defect in adaptive thermogenesis. Endocrinology 2010;151:4573-82.
Schneider MJ, Fiering SN, Pallud SE, Parlow AF, St Germain DL, Galton VA. Targeted disruption of the type 2 selenodeiodinase gene (DIO2) results in a phenotype of pituitary resistance to T4. Mol Endocrinol 2001;15:2137-48.
Silva JE, Larsen PR. Adrenergic activation of triiodothyronine production in brown adipose tissue. Nature 1983;305:712-3.
Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 1998;92:829-39.
Lin J, Wu PH, Tarr PT, Lindenberg KS, St-Pierre J, Zhang CY, et al.
Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1alpha null mice. Cell 2004;119:121-35.
Uldry M, Yang W, St-Pierre J, Lin J, Seale P, Spiegelman BM. Complementary action of the PGC-1 coactivators in mitochondrial biogenesis and brown fat differentiation. Cell Metab 2006;3:333-41.
Seale P, Conroe HM, Estall J, Kajimura S, Frontini A, Ishibashi J, et al.
Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice. J Clin Invest 2011;121:96-105.
Liu W, Bi P, Shan T, Yang X, Yin H, Wang YX, et al.
miR-133a regulates adipocyte browning in vivo
. PLoS Genet 2013;9:e1003626.
Ye L, Wu J, Cohen P, Kazak L, Khandekar MJ, Jedrychowski MP, et al.
Fat cells directly sense temperature to activate thermogenesis. Proc Natl Acad Sci U S A 2013;110:12480-5.
Cousin B, Cinti S, Morroni M, Raimbault S, Ricquier D, Pénicaud L, et al.
Occurrence of brown adipocytes in rat white adipose tissue: Molecular and morphological characterization. J Cell Sci 1992;103(Pt 4):931-42.
Barbatelli G, Murano I, Madsen L, Hao Q, Jimenez M, Kristiansen K, et al.
The emergence of cold-induced brown adipocytes in mouse white fat depots is determined predominantly by white to brown adipocyte transdifferentiation. Am J Physiol Endocrinol Metab 2010;298:E1244-53.
Wu J, Boström P, Sparks LM, Ye L, Choi JH, Giang AH, et al.
Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 2012;150:366-76.
Wang QA, Tao C, Gupta RK, Scherer PE. Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat Med 2013;19:1338-44.
Vosselman MJ, van der Lans AA, Brans B, Wierts R, van Baak MA, Schrauwen P, et al.
Systemic ß-adrenergic stimulation of thermogenesis is not accompanied by brown adipose tissue activity in humans. Diabetes 2012;61:3106-13.
Cypess AM, Chen YC, Sze C, Wang K, English J, Chan O, et al.
Cold but not sympathomimetics activates human brown adipose tissue in vivo
. Proc Natl Acad Sci U S A 2012;109:10001-5.
Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, et al.
A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012;481:463-8.
De Matteis R, Lucertini F, Guescini M, Polidori E, Zeppa S, Stocchi V, et al.
Exercise as a new physiological stimulus for brown adipose tissue activity. Nutr Metab Cardiovasc Dis 2013;23:582-90.
Iwami M, Alkayed F, Shiina T, Taira K, Shimizu Y. Activation of brown adipose tissue thermogenesis by electrical stimulation to the dorsal surface of the tissue in rats. Biomed Res 2013;34:173-8.
Raschke S, Elsen M, Gassenhuber H, Sommerfeld M, Schwahn U, Brockmann B, et al.
Evidence against a beneficial effect of irisin in humans. PLoS One 2013;8:e73680.
Sellers EA, Scott JW, Thomas N. Electrical activity of skeletal muscle of normal and acclimatized rats on exposure to cold. Am J Physiol 1954;177:372-6.
Carlson LD, Cottle WH. Regulation of heat production in cold-adapted rats. Proc Soc Exp Biol Med 1956;92:845-9.
Depocas F, Hart JS, Heroux O. Cold acclimation and the electromyogram of unanesthetized rats. J Appl Physiol 1956;9:404-8.
Smith RE. Thermoregulatory and adaptive behavior of brown adipose tissue. Science 1964;146:1686-9.
Cameron IL, Smith RE. Cytological responses of brown fat tissue in cold-exposed rats. J Cell Biol 1964;23:89-100.
Houstek J, Holub M. Cold-induced changes in brown adipose tissue thermogenic capacity of immunocompetent and immunodeficient hairless mice. J Comp Physiol B 1994;164:459-63.
Lee P, Brychta RJ, Linderman J, Smith S, Chen KY, Celi FS. Mild cold exposure modulates fibroblast growth factor 21 (FGF21) diurnal rhythm in humans: Relationship between FGF21 levels, lipolysis, and cold-induced thermogenesis. J Clin Endocrinol Metab 2013;98:E98-102.
Chen KY, Brychta RJ, Linderman JD, Smith S, Courville A, Dieckmann W, et al.
Brown fat activation mediates cold-induced thermogenesis in adult humans in response to a mild decrease in ambient temperature. J Clin Endocrinol Metab 2013;98:E1218-23.
Johnson F, Mavrogianni A, Ucci M, Vidal-Puig A, Wardle J. Could increased time spent in a thermal comfort zone contribute to population increases in obesity? Obes Rev 2011;12:543-51.
Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J, et al.
High incidence of metabolically active brown adipose tissue in healthy adult humans: Effects of cold exposure and adiposity. Diabetes 2009;58:1526-31.
Yoneshiro T, Aita S, Matsushita M, Kameya T, Nakada K, Kawai Y, et al.
Brown adipose tissue, whole-body energy expenditure, and thermogenesis in healthy adult men. Obesity (Silver Spring) 2011;19:13-6.
Celi FS, Brychta RJ, Linderman JD, Butler PW, Alberobello AT, Smith S, et al.
Minimal changes in environmental temperature result in a significant increase in energy expenditure and changes in the hormonal homeostasis in healthy adults. Eur J Endocrinol 2010;163:863-72.
Ouellet V, Routhier-Labadie A, Bellemare W, Lakhal-Chaieb L, Turcotte E, Carpentier AC, et al.
Outdoor temperature, age, sex, body mass index, and diabetic status determine the prevalence, mass, and glucose-uptake activity of 18F-FDG-detected BAT in humans. J Clin Endocrinol Metab 2011;96:192-9.
Yoneshiro T, Aita S, Matsushita M, Okamatsu-Ogura Y, Kameya T, Kawai Y, et al.
Age-related decrease in cold-activated brown adipose tissue and accumulation of body fat in healthy humans. Obesity (Silver Spring) 2011;19:1755-60.
Lan L, Cui G, Yang C, Wang J, Sui C, Xu G, et al.
Increased mortality during the 2010 heat wave in Harbin, China. Ecohealth 2012;9:310-4.
Lin H, Zhang Y, Xu Y, Xu X, Liu T, Luo Y, et al.
Temperature changes between neighboring days and mortality in summer: A distributed lag non-linear time series analysis. PLoS One 2013;8:e66403.
Choi GY, Choi JN, Kwon HJ. The impact of high apparent temperature on the increase of summertime disease-related mortality in Seoul: 1991-2000. J Prev Med Public Health 2005;38:283-90.
Tian Z, Li S, Zhang J, Jaakkola JJ, Guo Y. Ambient temperature and coronary heart disease mortality in Beijing, China: A time series study. Environ Health 2012;11:56.
[Table 1], [Table 2], [Table 3]