Coping with the stress: Expression of ATF4, ATF6, and downstream targets in organs of hibernating ground squirrels

Mamady, Hapsatou; Storey, Kenneth B.

doi:10.1016/j.abb.2008.05.006

Cited by 56 publications

(48 citation statements)

References 30 publications

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“…Accumulated evidence suggests that ATF4 plays an important role in regulation of the highlevel proliferation required during fetal-liver hematopoiesis [16], long-term memory [17][18][19], osteoblast differentiation [20], ER stress [21,22], amino acid deprivation [23] and glucose metabolism [24], etc. It has also been reported that ATF4 plays a key role in thermogenesis in BAT in small mammals [15]. There has been no report, however, that demonstrates a direct link between ATF4 and lipid metabolism.…”

Section: Introductionmentioning

confidence: 95%

“…It has been shown that ATF4 is constitutively expressed in a wide variety of tissues including brain, heart, WAT, BAT, liver, spleen, thymus, lung and kidney, as well as in cell lines derived from T cells, B cells, monocytes and fibroblasts [14,15]. Accumulated evidence suggests that ATF4 plays an important role in regulation of the highlevel proliferation required during fetal-liver hematopoiesis [16], long-term memory [17][18][19], osteoblast differentiation [20], ER stress [21,22], amino acid deprivation [23] and glucose metabolism [24], etc.…”

Section: Introductionmentioning

confidence: 99%

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ATF4 regulates lipid metabolism and thermogenesis

et al. 2010

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Activating transcription factor 4 (ATF4) has been shown to play key roles in many physiological processes. There are no reports, however, demonstrating a direct link between ATF4 and lipid metabolism. We noticed that Atf4-deficient mice are lean, suggesting a possible role for ATF4 in regulating lipid metabolism. The goal of our current study is to investigate the involvement of ATF4 in lipid metabolism and elucidate the underlying mechanisms. Studies using Atf4-deficient mice revealed increased energy expenditure, as measured by oxygen consumption. These mice also showed increases in lipolysis, expression of uncoupling protein 2 (UCP2) and β-oxidation genes and decreases in expression of lipogenic genes in white adipose tissue (WAT), suggesting increased utilization and decreased synthesis of fatty acids, respectively. Expression of UCP1, 2 and 3 was also increased in brown adipose tissue (BAT), suggesting increased thermogenesis. The effect of ATF4 deletion on expression of UCPs in BAT suggests that increased thermogenesis may underlie increased energy expenditure. Thus, our study identifies a possible new function for ATF4 in regulating lipid metabolism and thermogenesis.

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Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

ATF4 regulates lipid metabolism and thermogenesis

et al. 2010

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“…Up-regulation of selected genes under HIF-1 control may help hibernator organs deal with greatly reduced blood flow during torpor (ischemia) and/or apnoic breathing patterns that could cause hypoxia. Levels of the activating transcription factor (ATF4) also rose during hibernation in selected ground squirrel organs and, furthermore, the amount of ATF4 in the nucleus increased together with greatly enhanced nuclear levels of the ATF4 cofactor, the phosphorylated form of the cAMP response element-binding protein (CREB-1), strongly indicating increased transcription of genes under ATF4-pCREB-1 control (Mamady and Storey, 2008). One of the key actions of ATF4 is to enhance the expression of endoplasmic reticulum (ER) chaperone proteins and, indeed, both mRNA transcript and protein levels of the main ER chaperone, the glucose-regulated protein 78, increased strongly in brain and brown adipose tissue of hibernating ground squirrels, two organs that also showed strong increases in ATF4 and p-CREB-1 levels Storey, 2006, 2008).…”

Section: Transcriptional Control In Hibernationmentioning

confidence: 99%

Mammalian hibernation: differential gene expression and novel application of epigenetic controls

Morin¹,

Storey²

2009

Int. J. Dev. Biol.

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This review highlights current information about the regulatory mechanisms that govern gene expression during mammalian hibernation, in particular the potential role of epigenetic controls in coordinating the global suppression of transcription. Hibernation is characterized by long periods of deep torpor (when core body temperature drops to near ambient) that are interspersed with brief arousal periods back to euthermia. Entry into torpor requires coordinated controls which strongly suppress and reprioritize all metabolic functions, including global controls on both transcription and translation. At the same time, however, selected hibernation-specific genes are up-regulated under the control of specific transcription factors to support the torpid state; this includes genes that encode proteins involved in lipid fuel catabolism and in long term cytoprotection (e.g. antioxidants, chaperones). We evaluate the currently available information on global transcriptional suppression in hibernation and propose that epigenetic mechanisms such as DNA methylation, histone modification, SUMOylation and the actions of sirtuins play crucial roles in transcriptional suppression during torpor. Global controls providing translational suppression also occur during hibernation including reversible phosphorylation control of ribosomal initiation and elongation factors as well as polysome dissociation. We also present initial data that mRNA transcripts are regulated via inhibitory interactions with microRNA species during torpor and provide the first evidence of differential expression of miRNAs in hibernators. When taken together, these mechanisms provide hibernators with multiple layers of regulatory controls that achieve both global repression of gene expression and selected enhancement of genes/proteins that achieve the hibernation phenotype.

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“…gluconeogenesis and ketone body synthesis to provide fuel for the brain), whereas muscle, although inactive during most of a torpor bout, plays a key role in arousal by generating heat via shivering thermogenesis. Both tissues exhibit a range of transcriptional, translational and posttranscriptional changes during hibernation and metabolic depression (Abnous et al, 2008;Green et al, 1984;Mamady and Storey, 2008;Storey, 1987). As the transcriptional and translational response in hibernation involves global changes, we first evaluated genomic changes in DNA methylation and its conserved machinery.…”

Section: Introductionmentioning

confidence: 99%

Dynamic changes in global and gene specific DNA methylation during hibernation in adult thirteen-lined ground squirrels,Ictidomys tridecemlineatus

Alvarado

Mak

Liu

et al. 2015

Journal of Experimental Biology

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Hibernating mammals conserve energy in the winter by undergoing prolonged bouts of torpor, interspersed with brief arousals back to euthermia. These bouts are accompanied by a suite of reversible physiological and biochemical changes; however, much remains to be discovered about the molecular mechanisms involved. Given the seasonal nature of hibernation, it stands to reason that underlying plastic epigenetic mechanisms should exist. One such form of epigenomic regulation involves the reversible modification of cytosine bases in DNA by methylation. DNA methylation is well known to be a mechanism that confers upon DNA its cellular identity during differentiation in response to innate developmental cues. However, it has recently been hypothesized that DNA methylation also acts as a mechanism for adapting genome function to changing external environmental and experiential signals over different time scales, including during adulthood. Here, we tested the hypothesis that DNA methylation is altered during hibernation in adult wild animals. This study evaluated global changes in DNA methylation in response to hibernation in the liver and skeletal muscle of thirteen-lined ground squirrels along with changes in expression of DNA methyltransferases (DNMT1/3B) and methyl binding domain proteins (MBDs). A reduction in global DNA methylation occurred in muscle during torpor phases whereas significant changes in DNMTs and MBDs were seen in both tissues. We also report dynamic changes in DNA methylation in the promoter of the myocyte enhancer factor 2C (mef2c) gene, a candidate regulator of metabolism in skeletal muscle. Taken together, these data show that genomic DNA methylation is dynamic across torporarousal bouts during winter hibernation, consistent with a role for this regulatory mechanism in contributing to the hibernation phenotype.

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Coping with the stress: Expression of ATF4, ATF6, and downstream targets in organs of hibernating ground squirrels

Cited by 56 publications

References 30 publications

ATF4 regulates lipid metabolism and thermogenesis

ATF4 regulates lipid metabolism and thermogenesis

Mammalian hibernation: differential gene expression and novel application of epigenetic controls

Dynamic changes in global and gene specific DNA methylation during hibernation in adult thirteen-lined ground squirrels,Ictidomys tridecemlineatus

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