Mammals maintain a constant warm body temperature, facilitating a wide variety of metabolic reactions. Mammals that hibernate have the ability to slow their metabolism, which in turn reduces their ...body temperature and leads to a state of hypothermic torpor. For this metabolic rate reduction to occur on a whole-body scale, molecular interactions that change the physiology of cells, tissues and organs are required, resulting in a major departure from normal mammalian homeostasis. The aim of this Review is to cover recent advances in the molecular biology of mammalian hibernation, including the role of small molecules, seasonal changes in gene expression, cold-inducible RNA-binding proteins, the somatosensory system and emerging information on hibernating primates. To underscore the importance of differential gene expression across the hibernation cycle, mRNA levels for 14,261 ground squirrel genes during periods of activity and torpor are made available for several tissues via an interactive transcriptome browser. This Review also addresses recent findings on molecular interactions responsible for multi-day survival of near-freezing body temperatures, single-digit heart rates and a slowed metabolism that greatly reduces oxygen consumption. A better understanding of how natural hibernators survive these physiological extremes is beginning to lead to innovations in human medicine.
Mammalian hibernation presents a unique opportunity to study naturally occurring neuroprotection. Hibernating ground squirrels undergo rapid and extreme physiological changes in body temperature, ...oxygen consumption, and heart rate without suffering neurological damage from ischemia and reperfusion injury. Different brain regions show markedly different activity during the torpor/arousal cycle: the cerebral cortex shows activity only during the periodic returns to normothermia, while the hypothalamus is active over the entire temperature range. Therefore, region-specific neuroprotective strategies must exist to permit this compartmentalized spectrum of activity. In this study, we use the Illumina HiSeq platform to compare the transcriptomes of these two brain regions at four collection points across the hibernation season: April Active, October Active, Torpor, and IBA. In the cerebral cortex, 1,085 genes were found to be differentially expressed across collection points, while 1,063 genes were differentially expressed in the hypothalamus. Comparison of these transcripts indicates that the cerebral cortex and hypothalamus implement very different strategies during hibernation, showing less than 20% of these differentially expressed genes in common. The cerebral cortex transcriptome shows evidence of remodeling and plasticity during hibernation, including transcripts for the presynaptic cytomatrix proteins bassoon and piccolo, and extracellular matrix components, including laminins and collagens. Conversely, the hypothalamic transcriptome displays upregulation of transcripts involved in damage response signaling and protein turnover during hibernation, including the DNA damage repair gene RAD50 and ubiquitin E3 ligases UBR1 and UBR5. Additionally, the hypothalamus transcriptome also provides evidence of potential mechanisms underlying the hibernation phenotype, including feeding and satiety signaling, seasonal timing mechanisms, and fuel utilization. This study provides insight into potential neuroprotective strategies and hibernation control mechanisms, and also specifically shows that the hibernator brain exhibits both seasonal and regional differences in mRNA expression.
Brown adipose tissue (BAT) is a unique thermogenic tissue in mammals that rapidly produces heat via nonshivering thermogenesis. Small mammalian hibernators have evolved the greatest capacity for BAT ...because they use it to rewarm from hypothermic torpor numerous times throughout the hibernation season. Although hibernator BAT physiology has been investigated for decades, recent efforts have been directed toward understanding the molecular underpinnings of BAT regulation and function using a variety of methods, from mitochondrial functional assays to 'omics' approaches. As a result, the inner-workings of hibernator BAT are now being illuminated. In this Review, we discuss recent research progress that has identified players and pathways involved in brown adipocyte differentiation and maturation, as well as those involved in metabolic regulation. The unique phenotype of hibernation, and its reliance on BAT to generate heat to arouse mammals from torpor, has uncovered new molecular mechanisms and potential strategies for biomedical applications.
We used RNAseq to generate a comprehensive transcriptome of Brown Adipose Tissue (BAT) over the course of a year in the naturally hibernating thirteen-lined ground squirrel, Ictidomys ...tridecemlineatus. During hibernation ground squirrels do not feed and use fat stored in White Adipose Tissue (WAT) as their primary source of fuel. Stored lipid is consumed at high rates by BAT to generate heat at specific points during the hibernation season. The highest rate of BAT activity occurs during periodic arousals from hypothermic torpor bouts, referred to as Interbout Arousals (IBAs). IBAs are characterized by whole body re-warming (from 5 to 37 °C) in 2-3 hours, and provide a unique opportunity to determine the genes responsible for the highly efficient lipid oxidation and heat generation that drives the arousal process. Illumina HighSeq sequencing identified 14,573 distinct BAT mRNAs and quantified their levels at four points: active ground squirrels in April and October, and hibernating animals during both torpor and IBA. Based on significant changes in mRNA levels across the four collection points, 2,083 genes were shown to be differentially expressed. In addition to providing detail on the expression of nuclear genes encoding mitochondrial proteins, and genes involved in beta-adrenergic and lipolytic pathways, we identified differentially expressed genes encoding various transcription factors and other regulatory proteins which may play critical roles in high efficiency fat catabolism, non-shivering thermogenesis, and transitions into and out of the torpid state.
When faced with a harsh climate or inadequate food, some mammals enter a state of suspended animation known as torpor. A major goal of torpor research is to determine mechanisms that integrate ...environmental cues, gene expression and metabolism to produce periods of torpor lasting from hours to weeks. Recent discoveries spanning the Metazoa suggest that sirtuins, the mammalian circadian clock, fibroblast growth factor 21 (FGF21) and lipids are involved in torpor induction. For example, sirtuins link cellular energy status to the mammalian circadian clock, oxidative stress and metabolic fuel selection. In this review, we discuss how these recent discoveries form a new hypothesis linking changes in the physical environment with changes in the expression of genes that regulate torpor induction.
Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, Madison, Wisconsin; Department of Biology, University of Minnesota Duluth, Duluth, Minnesota; and ...Department of Cellular and Structural Biology, University of Colorado Health Sciences Center, Denver, Colorado
Carey, Hannah V., Matthew T. Andrews, and Sandra L. Martin. Mammalian Hibernation: Cellular and Molecular Responses to Depressed Metabolism and Low Temperature. Physiol Rev 83: 1153-1181, 2003; 10.1152/physrev. 00008.2003.Mammalian hibernators undergo a remarkable phenotypic switch that involves profound changes in physiology, morphology, and behavior in response to periods of unfavorable environmental conditions. The ability to hibernate is found throughout the class Mammalia and appears to involve differential expression of genes common to all mammals, rather than the induction of novel gene products unique to the hibernating state. The hibernation season is characterized by extended bouts of torpor, during which minimal body temperature (T b ) can fall as low as -2.9°C and metabolism can be reduced to 1% of euthermic rates. Many global biochemical and physiological processes exploit low temperatures to lower reaction rates but retain the ability to resume full activity upon rewarming. Other critical functions must continue at physiologically relevant levels during torpor and be precisely regulated even at T b values near 0°C. Research using new tools of molecular and cellular biology is beginning to reveal how hibernators survive repeated cycles of torpor and arousal during the hibernation season. Comprehensive approaches that exploit advances in genomic and proteomic technologies are needed to further define the differentially expressed genes that distinguish the summer euthermic from winter hibernating states. Detailed understanding of hibernation from the molecular to organismal levels should enable the translation of this information to the development of a variety of hypothermic and hypometabolic strategies to improve outcomes for human and animal health.
Address for reprint requests and other correspondence: H. V. Carey, Dept. of Comparative Biosciences, School of Veterinary Medicine, Univ. of Wisconsin, 2015 Linden Drive West, Madison, WI 53706 (E-mails: careyh{at}svm.vetmed.wisc.edu ).
UKESM1: Description and Evaluation of the U.K. Earth System Model Sellar, Alistair A.; Jones, Colin G.; Mulcahy, Jane P. ...
Journal of advances in modeling earth systems,
December 2019, 2019-12-00, 20191201, 2019-12-01, Letnik:
11, Številka:
12
Journal Article
Recenzirano
Odprti dostop
We document the development of the first version of the U.K. Earth System Model UKESM1. The model represents a major advance on its predecessor HadGEM2‐ES, with enhancements to all component models ...and new feedback mechanisms. These include a new core physical model with a well‐resolved stratosphere; terrestrial biogeochemistry with coupled carbon and nitrogen cycles and enhanced land management; tropospheric‐stratospheric chemistry allowing the holistic simulation of radiative forcing from ozone, methane, and nitrous oxide; two‐moment, five‐species, modal aerosol; and ocean biogeochemistry with two‐way coupling to the carbon cycle and atmospheric aerosols. The complexity of coupling between the ocean, land, and atmosphere physical climate and biogeochemical cycles in UKESM1 is unprecedented for an Earth system model. We describe in detail the process by which the coupled model was developed and tuned to achieve acceptable performance in key physical and Earth system quantities and discuss the challenges involved in mitigating biases in a model with complex connections between its components. Overall, the model performs well, with a stable pre‐industrial state and good agreement with observations in the latter period of its historical simulations. However, global mean surface temperature exhibits stronger‐than‐observed cooling from 1950 to 1970, followed by rapid warming from 1980 to 2014. Metrics from idealized simulations show a high climate sensitivity relative to previous generations of models: Equilibrium climate sensitivity is 5.4 K, transient climate response ranges from 2.68 to 2.85 K, and transient climate response to cumulative emissions is 2.49 to 2.66 K TtC−1.
Plain Language Summary
We describe the development and behavior of UKESM1, a novel climate model that includes improved representations of processes in the atmosphere, ocean, and on land. These processes are inter‐related: For example, dust is produced on the land and blown up into the atmosphere where it affects the amount of sunlight falling on Earth. Dust can also be dissolved in the ocean, where it affects marine life. This in turn changes both the amount of carbon dioxide absorbed by the ocean and the material emitted from the surface into the atmosphere, which has an affect on the formation of clouds. UKESM1 includes many processes and interactions such as these, giving it a high level of complexity. Ensuring realistic process behavior is a major challenge in the development of our model, and we have carefully tested this. UKESM1 performs well, correctly exhibiting stable results from a continuous pre‐industrial simulation (used to provide a reference for future experiments) and showing good agreement with observations toward the end of its historical simulations. Results for some properties—including the degree to which average surface temperature changes with increased amounts of carbon dioxide in the atmosphere—are examined in detail.
Key Points
UKESM1 represents a major advance over its predecessor HadGEM2‐ES, both in the complexity of its components and its internal coupling
The complex coupling presents challenges to the model development; we document the tuning process employed to obtain acceptable performance
UKESM1 performs well, having a stable pre‐industrial state and showing good agreement with observations in a wide variety of contexts
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