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Our ability to thermoregulate is a key physiological characteristic of humans and all other mammals. Therefore, exploring the physiological mechanisms underlying thermoregulation has been the focus of substantial scientific investigation for a number of years. Studies have ranged from those assessing the ability of humans to tolerate heat and cold stress in occupational, military, and recreational situations to the pathophysiology of heat and cold injuries. Certainly, in the clinical setting, it is widely recognized that fever is an important physiological response to systemic diseases and that body temperature manipulation can be used therapeutically. Other studies in the area of comparative physiology have examined unique conditions of thermoregulation, such as hibernation.

Although extensive knowledge exists from whole body, tissue and cellular studies, the application of molecular techniques holds great promise in unraveling the mysteries of physiological responses to heat and cold stress. For example, recent studies have demonstrated that cells from virtually all organisms respond to heat stress by the rapid synthesis of a highly conserved set of polypeptides termed heat shock proteins (HSPs). The precise function of HSPs remains unknown, but there is considerable evidence that these stress proteins are essential for survival at both normal and elevated temperatures. Far less is known about the molecular response(s) to cold stress, but perhaps lessons could be learned from comparative studies of hibernating mammals. This Highlighted Topics series focuses on the molecular biology of thermoregulation, featuring articles that encompass the breadth of gene expression, protein regulation, cytoprotection, cellular signaling, and metabolic regulation that underlie thermoregulatory physiology.

In the first mini-review of this Highlighted Topics series, entitled "Effects of heat and cold stress on mammalian gene expression," Dr. Larry Sonna and colleagues explore changes in gene expression induced by heat and cold stress. Cellular responses to heat stress have been extensively studied and are known to involve both changes in the activities of existing proteins as well as changes in gene expression, most notably expression of HSPs. Until recently, few genes other than those regulating expression of HSPs and chaperones had been shown to undergo heat-induced changes in expression (as defined by level of cellular mRNA). However, recent studies that used gene chip array technologies have made it apparent that the genomic response to heat stress is as complex as the proteomic response and involves changes in expression of genes in every major functional class previously identified as playing a role in the cellular response to heat. A growing body of literature also indicates that cells are capable of mounting a genomic response to cold stress. However, to date, relatively few genes have been clearly identified as responding to cold stress. In this respect, gene chip array studies may help identify candidate genes for further study.

Also in this issue is a mini-review entitled "Interplay between molecular chaperones and signaling pathways in survival of heat shock," by Drs. Vladimir Gabai and Michael Sherman. Exposure of mammalian cells to heat shock activates a number of signaling pathways. Some of these pathways are involved in cell survival, e.g., induction of molecular chaperones (HSP72, HSP27, and others), activation of extracellular-regulated protein kinase (ERK) and protein kinase B (also known as Akt), and phosphorylation of HSP27. On the other hand, heat shock also activates a stress kinase, c-Jun NH₂-terminal protein kinase (JNK), which triggers both apoptotic and nonapoptotic cell death. Recent data indicate that HSP72 and HSP27 can also modulate both cell death and survival pathways, via their function as molecular chaperones in refolding of stress-damaged proteins.

In the May issue, a mini-review entitled "Heat shock proteins: modifying factors in physiological stress responses and acquired thermotolerance," by Dr. Kevin C. Kregel will explore the factors that modify HSPs. Recent data show that HSPs play a critical role in the development of thermotolerance and protection from cellular damage associated with stresses such as ischemia, cytokines, and energy depletion. These observations suggest that HSPs are important in both normal cellular homeostasis and the stress response. This mini-review examines recent evidence and hypotheses, suggesting that the HSPs may be important modifying factors in cellular responses to a variety of physiologically relevant conditions such as exercise, hyperthermia, oxidative stress, metabolic challenge, and aging.

Also in May, a mini-review entitled "Uncoupling proteins and thermoregulation," by Drs. George Argyropoulos and Mary Ellen Harper, will examine current data and hypotheses concerning the role of uncoupling proteins (UCP1-5) in thermoregulation and energy balance. Many publications over the past three years have excited the scientific community and raised important new questions about uncoupling, proton leak, and mitochondrial biogenesis. This mini-review explores UCPs from genetic and physiological perspectives that have emanated from studies of humans and animal models. These authors bridge the diverse interpretations of currently available data and provide paradigms for future studies.

In the June issue, Drs. Sandra L. Martin and Frank van Breukelen explore the molecular adaptations that permit hibernation in a mini-review entitled "Molecular adaptations in mammalian hibernators: unique adaptations or generalized responses?" Hibernators are unique among mammals in their ability to withstand and reverse low body temperatures. Core temperatures reach as low as 2°C, are held there from 1 to 3 wk, and then quickly reverse to 37°C. This thermoregulatory cycle is repeated many times each winter. The fascinating physiological questions raised by the study of hibernating mammals relate to how these mammals maintain cardiac function, cell integrity, blood fluidity, and energetic balance during their prolonged periods at low body temperature. One possibility is that they are uniquely adapted at the molecular level to function at low temperature; however, this clearly cannot occur at the expense of function at normothermic temperatures.

Also in June, a mini-review entitled "Cytokine regulation of fever: studies using gene knockout mice," by Dr. Lisa R. Leon, explores fever, one of the most common responses to infection and inflammation. The cytokines interleukin (IL)-1, IL-6, IL-10, and tumor necrosis factor have been implicated as important mediators of this response. The injection of purified cytokines or their antagonists into laboratory animals has been a common method used to study fever. The recent development of gene knockout mice has provided a valuable tool to elucidate the role of cytokines in the febrile response. This mini-review examines current data from gene knockout mice and compares the results with those obtained using traditional pharmacological techniques. Several experimental models of fever are reviewed, including the injection of cytokines, lipopolysaccharide, turpentine, and cecal ligation and puncture.

A special feature of this Highlighted Topics series will be an invited editorial by Dr. David Baker, which will explore thermoregulatory dysfunction in multiple sclerosis and will appear in next month's issue of the Journal. Dr. Baker has been working for many years as a research physiologist, and this editorial has been prepared from knowledge gained by Dr. Baker from his own experience of living with multiple sclerosis and its heat-related symptoms. In his editorial, Dr. Baker draws attention to three areas where further research may have important implications to those living and coping with multiple sclerosis: thermoregulatory failure, cranial radiator, and exercise-induced heat. The Associate Editors and I hope that this invited editorial as well as the invited mini-reviews to be published in the coming months will stimulate further research in this vitally important area of applied physiology.

Obviously, the featured articles in this Highlighted Topics series reflect only the beginning of a better understanding of the molecular mechanisms underlying thermoregulation. As with past Highlighted Topics series, the Associate Editors and I strongly encourage submission of original research in this area of applied physiology both now and in the future.