The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

John R Speakman - One of the best experts on this subject based on the ideXlab platform.

  • associations between energetics and over winter survival in the short tailed field vole microtus agrestis
    Journal of Animal Ecology, 2001
    Co-Authors: John R Speakman, Diane M Jackson, P Trayhurn
    Abstract:

    Summary 1  Over-winter mortality in small mammals is influenced strongly by low ambient temperatures. Individuals with greater thermogenic capacities might then be expected to survive better than those with lower thermogenic capacities. 2  To test this hypothesis, short-tailed field voles Microtus agrestis (Linnaeus) were captured during the winters of 1995/96 and 1996/97 at two field sites near Aberdeen (57°N). The captured animals were tagged and taken back to the laboratory, where their resting metabolism (RMR), thermogenic capacity (NA induced metabolism excluding RMR) and body mass were measured. 3  Body mass, RMR and thermogenic capacity did not differ significantly between the start and end of winter in voles that were captured at both times. 4  Body mass varied significantly over the winter months, being lowest in January and highest in March. Thermogenic capacity also varied over the winter and the variation was linked significantly with changes in ambient temperature, suggesting that either voles with greater thermogenic capacity were more likely to be active on cold nights, or voles were flexible in their thermogenic capacities. RMR did not vary significantly over the winter. 5  Animals that survived the winter had a significantly higher residual RMR than those that died (or permanently emigrated) but the survivors did not have significantly greater body masses, RMRs, thermogenic capacities or residual thermogenic capacities.

  • long photophase is not a sufficient stimulus to reduce thermogenic capacity in winter acclimatized short tailed field voles microtus agrestis during long term cold acclimation
    Journal of Comparative Physiology B-biochemical Systemic and Environmental Physiology, 1994
    Co-Authors: R M Mcdevitt, John R Speakman
    Abstract:

    The thermogenic capacity of brown adipose tissue in winter- and summer-acclimatized short-tailed field voles (Microtus agrestis) was investigated by examining changes in mass of brown adipose tissue, the ratio of white adipose tissue to brown adipose tissue, the concentration of the uncoupling protein (Thermogenin) in whole depots (μg) and in mitochondrial mass (μg·mg-1) and the activity of cytochrome c oxidase in the depots (mmol·min-1). The concentration of Thermogenin in winter-acclimatized voles (n=8), per brown adipose tissue depot and per mitochondrial mass, was significantly higher than in summer-acclimatized voles (n=6). There was no significant difference in the level of cytochrome c oxidase activity between these two groups. Four groups of winter-acclimatized voles (n=6 in each group) were exposed to 5°C for 10, 20, 50 and 100 days in a 14L:10D photoperiod. Body mass, brown adipose tissue mass, white adipose tissue mass and basal metabolic rate were significantly positively related to the length of time cold exposed up to 100 days. There was a significant inverse relationship between the ratio of white to brown adipose tissue mass and the duration of cold exposure. There was no significant relationship between Thermogenin concentration, either per depot or in mitochondrial mass of brown adipose tissue, with the length of time cold exposed. The level of cytochrome c oxidase activity increased significantly from control levels to a maximum after 10 days in the cold but decreased from 10 days onwards. In winter-acclimatized M. agrestis, a 14L:10D photoperiod is not a sufficient stimulus to reduce thermogenic capacity during cold acclimation. Indeed, some changes in the indirect parameters reflecting thermogenesis, notably the increase in basal metabolic rate and the decrease in the ratio of white to brown adipose tissue mass, indicated that despite the long photophase the thermogenic capacity was slightly further enhanced during the cold acclimation.

Jan Nedergaard - One of the best experts on this subject based on the ideXlab platform.

  • promotion of lipid storage rather than of thermogenic competence by fetal versus newborn calf serum in primary cultures of brown adipocytes
    Adipocyte, 2018
    Co-Authors: Jasper M A De Jong, Barbara Cannon, Jan Nedergaard
    Abstract:

    Much current understanding of brown adipocyte development comes from in-vitro cell models. Serum type may affect the behavior of cultured cells and thus conclusions drawn. Here, we investigate effects of serum type (“fetal bovine” versus “newborn calf”) on responses to differentiation inducers (the PPARγ agonist rosiglitazone or the neurotransmitter norepinephrine) in cultured primary brown adipocytes. Lipid storage was enhanced by fetal versus newborn serum. However, molecular adipose conversion ( Pparg2 and Fabp4 expression) was not affected by serum type. Rosiglitazone-induced (7-days) expression of thermogenic genes (i.e. Ucp1, Pgc1a, Dio2 and Elovl3 ) was not systematically affected by serum type. However, importantly, acute (2 h) norepinephrine-induced thermogenic gene expression was overall markedly higher (and adipose genes somewhat lower) in cells cultured in newborn serum. Thus, newborn serum promotes thermogenic competence, and the use of fetal serum in brown adipocyte cultures (as is often routine) counteracts adequate differentiation. Agents that counteract this inhibition may therefore confoundingly be ascribed genuine thermogenic competence-inducing properties.

  • thermogenic responses in brown fat cells are fully ucp1 dependent ucp2 or ucp3 do not substitute for ucp1 in adrenergically or fatty acid induced thermogenesis
    Journal of Biological Chemistry, 2000
    Co-Authors: Anita Matthias, Jan Nedergaard, Anders Jacobsson, Kerstin B E Ohlson, Magnus J Fredriksson, Barbara Cannon
    Abstract:

    Abstract To examine the thermogenic significance of the classical uncoupling protein-1 (UCP1), the thermogenic potential of brown adipocytes isolated from UCP1-ablated mice was investigated.Ucp1(−/−) cells had a basal metabolic rate identical to wild-type; the mitochondria within them were coupled to the same degree. The response to norepinephrine in wild-type cells was robust (≈10-fold increase in thermogenesis);Ucp1(−/−) cells only responded ≈3% of this. Ucp1(−/−) cells were as potent as wild-type in norepinephrine-induced cAMP accumulation and lipolysis and had a similar mitochondrial respiratory complement. In wild-type cells, fatty acids induced a thermogenic response similar to norepinephrine, but fatty acids (and retinoate) were practically without effect inUcp1(−/−) cells. It is concluded that no other adrenergically induced thermogenic mechanism exists in brown adipocytes except that mediated by UCP1 and that entopic expression of UCP1 does not lead to overt innate uncoupling, and it is suggested that fatty acids are transformed to an intracellular physiological activator of UCP1. High expression of UCP2 and UCP3 in the tissue was not associated with an overt innate highly uncoupled state of mitochondria within the cells, nor with an ability of norepinephrine or endo- or exogenous fatty acids to induce uncoupled respiration in the cells. Thus, UCP1 remains the only physiologically potent thermogenic uncoupling protein in these cells.

  • thermogenic responses in brown fat cells are fully ucp1 dependent ucp2 or ucp3 do not substitute for ucp1 in adrenergically or fatty scid induced thermogenesis
    Journal of Biological Chemistry, 2000
    Co-Authors: Anita Matthias, Jan Nedergaard, Anders Jacobsson, Kerstin B E Ohlson, J M Fredriksson, Barbara Cannon
    Abstract:

    To examine the thermogenic significance of the classical uncoupling protein-1 (UCP1), the thermogenic potential of brown adipocytes isolated from UCP1-ablated mice was investigated. Ucp1(-/-) cells had a basal metabolic rate identical to wild-type; the mitochondria within them were coupled to the same degree. The response to norepinephrine in wild-type cells was robust ( approximately 10-fold increase in thermogenesis); Ucp1(-/-) cells only responded approximately 3% of this. Ucp1(-/-) cells were as potent as wild-type in norepinephrine-induced cAMP accumulation and lipolysis and had a similar mitochondrial respiratory complement. In wild-type cells, fatty acids induced a thermogenic response similar to norepinephrine, but fatty acids (and retinoate) were practically without effect in Ucp1(-/-) cells. It is concluded that no other adrenergically induced thermogenic mechanism exists in brown adipocytes except that mediated by UCP1 and that entopic expression of UCP1 does not lead to overt innate uncoupling, and it is suggested that fatty acids are transformed to an intracellular physiological activator of UCP1. High expression of UCP2 and UCP3 in the tissue was not associated with an overt innate highly uncoupled state of mitochondria within the cells, nor with an ability of norepinephrine or endo- or exogenous fatty acids to induce uncoupled respiration in the cells. Thus, UCP1 remains the only physiologically potent thermogenic uncoupling protein in these cells.

  • the uncoupling protein Thermogenin during acclimation indications for pretranslational control
    American Journal of Physiology-regulatory Integrative and Comparative Physiology, 1994
    Co-Authors: Anders Jacobsson, Barbara Cannon, M Muhleisen, Jan Nedergaard
    Abstract:

    To analyze the regulation of the content of the uncoupling protein Thermogenin in brown adipose tissue, we have selected a physiological transition phase during which to investigate the relationship between the level of mRNA and the level of the ensuing protein product. Mice preacclimated to 28 degrees C were transferred to 4 degrees C. Cold acclimation led to the expected increases in brown fat total protein and RNA content. Two recruited proteins were analyzed: the cytosolic glycerol-3-phosphate dehydrogenase and the mitochondrial uncoupling protein Thermogenin. The activity of the dehydrogenase acutely followed the level of the corresponding mRNA, indicating pretranslational control. However, for Thermogenin there was a marked time delay between the establishment of the fully recruited level of Thermogenin mRNA (after only approximately 4 h of cold exposure) and that of Thermogenin itself (after > 3 wk). By reiterative computer simulation, it was investigated whether a model only involving pretranslational regulation could be invoked for either system. For glycerol-phosphate dehydrogenase, a plausible model could be constructed, provided the protein half-life was shorter than approximately 24 h. Despite the long time delay between full Thermogenin mRNA recruitment and full Thermogenin protein recruitment, a plausible pretranslational control model could also be constructed, provided that the protein half-life was approximately 5 days. This computed value was in good agreement with the half-life obtained from independent Thermogenin half-life studies. It is implied that pretranslational control may suffice to explain the regulation of Thermogenin content in brown adipose tissue during a warm-to-cold transition period.

  • stabilization of the mrna for the uncoupling protein Thermogenin by transcriptional translational blockade and by noradrenaline in brown adipocytes differentiated in culture a degradation factor induced by cessation of stimulation
    Biochemical Journal, 1994
    Co-Authors: Catalina Picó, Barbara Cannon, Anders Jacobsson, Andreu Palou, D Herron, Jan Nedergaard
    Abstract:

    The stability of the mRNA coding for the uncoupling protein Thermogenin was investigated in mouse brown-fat cells differentiated in culture. After 7 days in culture, the cells were stimulated for 24 h with noradrenaline, and a high level of Thermogenin mRNA was then observed. If noradrenaline treatment was continued, the mRNA level remained high, but, upon withdrawal of noradrenaline, the level decreased rapidly, with a half-life of only 2.7 h. The presence of transcriptional (actinomycin) or translational (cycloheximide) inhibitors prolonged the apparent half-life by about 50%. The presence of noradrenaline during transcriptional blockade led to a further stabilization of Thermogenin mRNA. It was concluded that an induced (or short-lived) gene product is important for Thermogenin mRNA degradation. Direct interaction of noradrenaline with the cultured brown adipocytes could apparently not mimic the paradoxical destabilization of Thermogenin mRNA in vivo, previously observed in the cold-exposed mouse [Jacobsson, Cannon and Nedergaard (1987) FEBS Lett. 244, 353-356], indicating significant differences between the systems in vitro and in vivo.

Joseph A Baur - One of the best experts on this subject based on the ideXlab platform.

  • histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge
    Nature, 2017
    Co-Authors: Matthew J Emmett, Jennifer Jager, Hannah J Richter, Marine Adlanmerini, Lindsey C Peed, Erika R Briggs, David J Steger, Carrie A Sims, Joseph A Baur, Patrick Seale
    Abstract:

    Histone deacetylase 3 (HDAC3) is required to activate brown adipose tissue enhancers to ensure thermogenic aptitude. Brown adipose tissue (BAT), or brown fat, protects against hypothermia by generating heat. Mitchell Lazar and colleagues discovered a critical and novel role of the epigenetic modulator HDAC3 in controlling the ability of BAT to respond to acute thermogenic challenges. They report that histone deacetylase 3 (HDAC3) acts in BAT as a transcriptional coactivator to ensure basal transcription of BAT-specific genes, independent of adrenergic stimulation. HDAC3 primes UCP1 and the thermogenic transcriptional program to maintain a critical capacity for thermogenesis in BAT that can be rapidly engaged for thermogenic respiration and heat production on demand. This improves our understanding of the physiological basis for mammalian response to extreme cold exposure. Brown adipose tissue is a thermogenic organ that dissipates chemical energy as heat to protect animals against hypothermia and to counteract metabolic disease1. However, the transcriptional mechanisms that determine the thermogenic capacity of brown adipose tissue before environmental cold are unknown. Here we show that histone deacetylase 3 (HDAC3) is required to activate brown adipose tissue enhancers to ensure thermogenic aptitude. Mice with brown adipose tissue-specific genetic ablation of HDAC3 become severely hypothermic and succumb to acute cold exposure. Uncoupling protein 1 (UCP1) is nearly absent in brown adipose tissue lacking HDAC3, and there is also marked downregulation of mitochondrial oxidative phosphorylation genes resulting in diminished mitochondrial respiration. Remarkably, although HDAC3 acts canonically as a transcriptional corepressor2, it functions as a coactivator of oestrogen-related receptor α (ERRα) in brown adipose tissue. HDAC3 coactivation of ERRα is mediated by deacetylation of PGC-1α and is required for the transcription of Ucp1, Ppargc1a (encoding PGC-1α), and oxidative phosphorylation genes. Importantly, HDAC3 promotes the basal transcription of these genes independently of adrenergic stimulation. Thus, HDAC3 uniquely primes Ucp1 and the thermogenic transcriptional program to maintain a critical capacity for thermogenesis in brown adipose tissue that can be rapidly engaged upon exposure to dangerously cold temperature.

  • histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge
    Nature, 2017
    Co-Authors: Matthew J Emmett, Jennifer Jager, Hannah J Richter, Marine Adlanmerini, Lindsey C Peed, Erika R Briggs, David J Steger, Carrie A Sims, Heewoong Lim, Joseph A Baur
    Abstract:

    Brown adipose tissue is a thermogenic organ that dissipates chemical energy as heat to protect animals against hypothermia and to counteract metabolic disease. However, the transcriptional mechanisms that determine the thermogenic capacity of brown adipose tissue before environmental cold are unknown. Here we show that histone deacetylase 3 (HDAC3) is required to activate brown adipose tissue enhancers to ensure thermogenic aptitude. Mice with brown adipose tissue-specific genetic ablation of HDAC3 become severely hypothermic and succumb to acute cold exposure. Uncoupling protein 1 (UCP1) is nearly absent in brown adipose tissue lacking HDAC3, and there is also marked downregulation of mitochondrial oxidative phosphorylation genes resulting in diminished mitochondrial respiration. Remarkably, although HDAC3 acts canonically as a transcriptional corepressor, it functions as a coactivator of oestrogen-related receptor α (ERRα) in brown adipose tissue. HDAC3 coactivation of ERRα is mediated by deacetylation of PGC-1α and is required for the transcription of Ucp1, Ppargc1a (encoding PGC-1α), and oxidative phosphorylation genes. Importantly, HDAC3 promotes the basal transcription of these genes independently of adrenergic stimulation. Thus, HDAC3 uniquely primes Ucp1 and the thermogenic transcriptional program to maintain a critical capacity for thermogenesis in brown adipose tissue that can be rapidly engaged upon exposure to dangerously cold temperature.

Barbara Cannon - One of the best experts on this subject based on the ideXlab platform.

  • promotion of lipid storage rather than of thermogenic competence by fetal versus newborn calf serum in primary cultures of brown adipocytes
    Adipocyte, 2018
    Co-Authors: Jasper M A De Jong, Barbara Cannon, Jan Nedergaard
    Abstract:

    Much current understanding of brown adipocyte development comes from in-vitro cell models. Serum type may affect the behavior of cultured cells and thus conclusions drawn. Here, we investigate effects of serum type (“fetal bovine” versus “newborn calf”) on responses to differentiation inducers (the PPARγ agonist rosiglitazone or the neurotransmitter norepinephrine) in cultured primary brown adipocytes. Lipid storage was enhanced by fetal versus newborn serum. However, molecular adipose conversion ( Pparg2 and Fabp4 expression) was not affected by serum type. Rosiglitazone-induced (7-days) expression of thermogenic genes (i.e. Ucp1, Pgc1a, Dio2 and Elovl3 ) was not systematically affected by serum type. However, importantly, acute (2 h) norepinephrine-induced thermogenic gene expression was overall markedly higher (and adipose genes somewhat lower) in cells cultured in newborn serum. Thus, newborn serum promotes thermogenic competence, and the use of fetal serum in brown adipocyte cultures (as is often routine) counteracts adequate differentiation. Agents that counteract this inhibition may therefore confoundingly be ascribed genuine thermogenic competence-inducing properties.

  • thermogenic responses in brown fat cells are fully ucp1 dependent ucp2 or ucp3 do not substitute for ucp1 in adrenergically or fatty acid induced thermogenesis
    Journal of Biological Chemistry, 2000
    Co-Authors: Anita Matthias, Jan Nedergaard, Anders Jacobsson, Kerstin B E Ohlson, Magnus J Fredriksson, Barbara Cannon
    Abstract:

    Abstract To examine the thermogenic significance of the classical uncoupling protein-1 (UCP1), the thermogenic potential of brown adipocytes isolated from UCP1-ablated mice was investigated.Ucp1(−/−) cells had a basal metabolic rate identical to wild-type; the mitochondria within them were coupled to the same degree. The response to norepinephrine in wild-type cells was robust (≈10-fold increase in thermogenesis);Ucp1(−/−) cells only responded ≈3% of this. Ucp1(−/−) cells were as potent as wild-type in norepinephrine-induced cAMP accumulation and lipolysis and had a similar mitochondrial respiratory complement. In wild-type cells, fatty acids induced a thermogenic response similar to norepinephrine, but fatty acids (and retinoate) were practically without effect inUcp1(−/−) cells. It is concluded that no other adrenergically induced thermogenic mechanism exists in brown adipocytes except that mediated by UCP1 and that entopic expression of UCP1 does not lead to overt innate uncoupling, and it is suggested that fatty acids are transformed to an intracellular physiological activator of UCP1. High expression of UCP2 and UCP3 in the tissue was not associated with an overt innate highly uncoupled state of mitochondria within the cells, nor with an ability of norepinephrine or endo- or exogenous fatty acids to induce uncoupled respiration in the cells. Thus, UCP1 remains the only physiologically potent thermogenic uncoupling protein in these cells.

  • thermogenic responses in brown fat cells are fully ucp1 dependent ucp2 or ucp3 do not substitute for ucp1 in adrenergically or fatty scid induced thermogenesis
    Journal of Biological Chemistry, 2000
    Co-Authors: Anita Matthias, Jan Nedergaard, Anders Jacobsson, Kerstin B E Ohlson, J M Fredriksson, Barbara Cannon
    Abstract:

    To examine the thermogenic significance of the classical uncoupling protein-1 (UCP1), the thermogenic potential of brown adipocytes isolated from UCP1-ablated mice was investigated. Ucp1(-/-) cells had a basal metabolic rate identical to wild-type; the mitochondria within them were coupled to the same degree. The response to norepinephrine in wild-type cells was robust ( approximately 10-fold increase in thermogenesis); Ucp1(-/-) cells only responded approximately 3% of this. Ucp1(-/-) cells were as potent as wild-type in norepinephrine-induced cAMP accumulation and lipolysis and had a similar mitochondrial respiratory complement. In wild-type cells, fatty acids induced a thermogenic response similar to norepinephrine, but fatty acids (and retinoate) were practically without effect in Ucp1(-/-) cells. It is concluded that no other adrenergically induced thermogenic mechanism exists in brown adipocytes except that mediated by UCP1 and that entopic expression of UCP1 does not lead to overt innate uncoupling, and it is suggested that fatty acids are transformed to an intracellular physiological activator of UCP1. High expression of UCP2 and UCP3 in the tissue was not associated with an overt innate highly uncoupled state of mitochondria within the cells, nor with an ability of norepinephrine or endo- or exogenous fatty acids to induce uncoupled respiration in the cells. Thus, UCP1 remains the only physiologically potent thermogenic uncoupling protein in these cells.

  • the uncoupling protein Thermogenin during acclimation indications for pretranslational control
    American Journal of Physiology-regulatory Integrative and Comparative Physiology, 1994
    Co-Authors: Anders Jacobsson, Barbara Cannon, M Muhleisen, Jan Nedergaard
    Abstract:

    To analyze the regulation of the content of the uncoupling protein Thermogenin in brown adipose tissue, we have selected a physiological transition phase during which to investigate the relationship between the level of mRNA and the level of the ensuing protein product. Mice preacclimated to 28 degrees C were transferred to 4 degrees C. Cold acclimation led to the expected increases in brown fat total protein and RNA content. Two recruited proteins were analyzed: the cytosolic glycerol-3-phosphate dehydrogenase and the mitochondrial uncoupling protein Thermogenin. The activity of the dehydrogenase acutely followed the level of the corresponding mRNA, indicating pretranslational control. However, for Thermogenin there was a marked time delay between the establishment of the fully recruited level of Thermogenin mRNA (after only approximately 4 h of cold exposure) and that of Thermogenin itself (after > 3 wk). By reiterative computer simulation, it was investigated whether a model only involving pretranslational regulation could be invoked for either system. For glycerol-phosphate dehydrogenase, a plausible model could be constructed, provided the protein half-life was shorter than approximately 24 h. Despite the long time delay between full Thermogenin mRNA recruitment and full Thermogenin protein recruitment, a plausible pretranslational control model could also be constructed, provided that the protein half-life was approximately 5 days. This computed value was in good agreement with the half-life obtained from independent Thermogenin half-life studies. It is implied that pretranslational control may suffice to explain the regulation of Thermogenin content in brown adipose tissue during a warm-to-cold transition period.

  • stabilization of the mrna for the uncoupling protein Thermogenin by transcriptional translational blockade and by noradrenaline in brown adipocytes differentiated in culture a degradation factor induced by cessation of stimulation
    Biochemical Journal, 1994
    Co-Authors: Catalina Picó, Barbara Cannon, Anders Jacobsson, Andreu Palou, D Herron, Jan Nedergaard
    Abstract:

    The stability of the mRNA coding for the uncoupling protein Thermogenin was investigated in mouse brown-fat cells differentiated in culture. After 7 days in culture, the cells were stimulated for 24 h with noradrenaline, and a high level of Thermogenin mRNA was then observed. If noradrenaline treatment was continued, the mRNA level remained high, but, upon withdrawal of noradrenaline, the level decreased rapidly, with a half-life of only 2.7 h. The presence of transcriptional (actinomycin) or translational (cycloheximide) inhibitors prolonged the apparent half-life by about 50%. The presence of noradrenaline during transcriptional blockade led to a further stabilization of Thermogenin mRNA. It was concluded that an induced (or short-lived) gene product is important for Thermogenin mRNA degradation. Direct interaction of noradrenaline with the cultured brown adipocytes could apparently not mimic the paradoxical destabilization of Thermogenin mRNA in vivo, previously observed in the cold-exposed mouse [Jacobsson, Cannon and Nedergaard (1987) FEBS Lett. 244, 353-356], indicating significant differences between the systems in vitro and in vivo.

Matthew J Emmett - One of the best experts on this subject based on the ideXlab platform.

  • histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge
    Nature, 2017
    Co-Authors: Matthew J Emmett, Jennifer Jager, Hannah J Richter, Marine Adlanmerini, Lindsey C Peed, Erika R Briggs, David J Steger, Carrie A Sims, Joseph A Baur, Patrick Seale
    Abstract:

    Histone deacetylase 3 (HDAC3) is required to activate brown adipose tissue enhancers to ensure thermogenic aptitude. Brown adipose tissue (BAT), or brown fat, protects against hypothermia by generating heat. Mitchell Lazar and colleagues discovered a critical and novel role of the epigenetic modulator HDAC3 in controlling the ability of BAT to respond to acute thermogenic challenges. They report that histone deacetylase 3 (HDAC3) acts in BAT as a transcriptional coactivator to ensure basal transcription of BAT-specific genes, independent of adrenergic stimulation. HDAC3 primes UCP1 and the thermogenic transcriptional program to maintain a critical capacity for thermogenesis in BAT that can be rapidly engaged for thermogenic respiration and heat production on demand. This improves our understanding of the physiological basis for mammalian response to extreme cold exposure. Brown adipose tissue is a thermogenic organ that dissipates chemical energy as heat to protect animals against hypothermia and to counteract metabolic disease1. However, the transcriptional mechanisms that determine the thermogenic capacity of brown adipose tissue before environmental cold are unknown. Here we show that histone deacetylase 3 (HDAC3) is required to activate brown adipose tissue enhancers to ensure thermogenic aptitude. Mice with brown adipose tissue-specific genetic ablation of HDAC3 become severely hypothermic and succumb to acute cold exposure. Uncoupling protein 1 (UCP1) is nearly absent in brown adipose tissue lacking HDAC3, and there is also marked downregulation of mitochondrial oxidative phosphorylation genes resulting in diminished mitochondrial respiration. Remarkably, although HDAC3 acts canonically as a transcriptional corepressor2, it functions as a coactivator of oestrogen-related receptor α (ERRα) in brown adipose tissue. HDAC3 coactivation of ERRα is mediated by deacetylation of PGC-1α and is required for the transcription of Ucp1, Ppargc1a (encoding PGC-1α), and oxidative phosphorylation genes. Importantly, HDAC3 promotes the basal transcription of these genes independently of adrenergic stimulation. Thus, HDAC3 uniquely primes Ucp1 and the thermogenic transcriptional program to maintain a critical capacity for thermogenesis in brown adipose tissue that can be rapidly engaged upon exposure to dangerously cold temperature.

  • histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge
    Nature, 2017
    Co-Authors: Matthew J Emmett, Jennifer Jager, Hannah J Richter, Marine Adlanmerini, Lindsey C Peed, Erika R Briggs, David J Steger, Carrie A Sims, Heewoong Lim, Joseph A Baur
    Abstract:

    Brown adipose tissue is a thermogenic organ that dissipates chemical energy as heat to protect animals against hypothermia and to counteract metabolic disease. However, the transcriptional mechanisms that determine the thermogenic capacity of brown adipose tissue before environmental cold are unknown. Here we show that histone deacetylase 3 (HDAC3) is required to activate brown adipose tissue enhancers to ensure thermogenic aptitude. Mice with brown adipose tissue-specific genetic ablation of HDAC3 become severely hypothermic and succumb to acute cold exposure. Uncoupling protein 1 (UCP1) is nearly absent in brown adipose tissue lacking HDAC3, and there is also marked downregulation of mitochondrial oxidative phosphorylation genes resulting in diminished mitochondrial respiration. Remarkably, although HDAC3 acts canonically as a transcriptional corepressor, it functions as a coactivator of oestrogen-related receptor α (ERRα) in brown adipose tissue. HDAC3 coactivation of ERRα is mediated by deacetylation of PGC-1α and is required for the transcription of Ucp1, Ppargc1a (encoding PGC-1α), and oxidative phosphorylation genes. Importantly, HDAC3 promotes the basal transcription of these genes independently of adrenergic stimulation. Thus, HDAC3 uniquely primes Ucp1 and the thermogenic transcriptional program to maintain a critical capacity for thermogenesis in brown adipose tissue that can be rapidly engaged upon exposure to dangerously cold temperature.