The Experts below are selected from a list of 16683 Experts worldwide ranked by ideXlab platform
Shingo Kajimura - One of the best experts on this subject based on the ideXlab platform.
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Mitochondrial Patch Clamp of Beige Adipocytes Reveals UCP1-Positive and UCP1-Negative Cells Both Exhibiting Futile Creatine Cycling
Cell metabolism, 2017Co-Authors: Ambre M Bertholet, Shingo Kajimura, Lawrence Kazak, Edward T Chouchani, Marta G. Bogaczynska, Ishan Paranjpe, Gabrielle L. Wainwright, Alexandre Betourne, Bruce M. Spiegelman, Yuriy KirichokAbstract:Summary Cold and other environmental factors induce "browning" of white fat depots—development of Beige adipocytes with morphological and functional resemblance to brown fat. Similar to brown fat, Beige adipocytes are assumed to express mitochondrial uncoupling protein 1 (UCP1) and are thermogenic due to the UCP1-mediated H + leak across the inner mitochondrial membrane. However, this assumption has never been tested directly. Herein we patch clamped the inner mitochondrial membrane of Beige and brown fat to provide a direct comparison of their thermogenic H + leak ( I H ). All inguinal Beige adipocytes had robust UCP1-dependent I H comparable to brown fat, but it was about three times less sensitive to purine nucleotide inhibition. Strikingly, only ∼15% of epididymal Beige adipocytes had I H , while in the rest UCP1-dependent I H was undetectable. Despite the absence of UCP1 in the majority of epididymal Beige adipocytes, these cells employ prominent creatine cycling as a UCP1-independent thermogenic mechanism.
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Beige Adipocyte Maintenance Is Regulated by Autophagy-Induced Mitochondrial Clearance
Cell metabolism, 2016Co-Authors: Svetlana Altshuler-keylin, Kosaku Shinoda, Yutaka Hasegawa, Kenji Ikeda, Haemin Hong, Qianqian Kang, Yangyu Yang, Rushika M. Perera, Jayanta Debnath, Shingo KajimuraAbstract:Beige adipocytes gained much attention as an alternative cellular target in anti-obesity therapy. While recent studies have identified a number of regulatory circuits that promote Beige adipocyte differentiation, the molecular basis of Beige adipocyte maintenance remains unknown. Here, we demonstrate that Beige adipocytes progressively lose their morphological and molecular characteristics after withdrawing external stimuli and directly acquire white-like characteristics bypassing an intermediate precursor stage. The Beige-to-white adipocyte transition is tightly coupled to a decrease in mitochondria, increase in autophagy, and activation of MiT/TFE transcription factor-mediated lysosome biogenesis. The autophagy pathway is crucial for mitochondrial clearance during the transition; inhibiting autophagy by uncoupled protein 1 (UCP1(+))-adipocyte-specific deletion of Atg5 or Atg12 prevents Beige adipocyte loss after withdrawing external stimuli, maintaining high thermogenic capacity and protecting against diet-induced obesity and insulin resistance. The present study uncovers a fundamental mechanism by which autophagy-mediated mitochondrial clearance controls Beige adipocyte maintenance, thereby providing new opportunities to counteract obesity.
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transcriptional and epigenetic control of brown and Beige adipose cell fate and function
Nature Reviews Molecular Cell Biology, 2016Co-Authors: Takeshi Inagaki, Juro Sakai, Shingo KajimuraAbstract:White adipocytes store excess energy in the form of triglycerides, whereas brown and Beige adipocytes dissipate energy in the form of heat. This thermogenic function relies on the activation of brown and Beige adipocyte-specific gene programmes that are coordinately regulated by adipose-selective chromatin architectures and by a set of unique transcriptional and epigenetic regulators. A number of transcriptional and epigenetic regulators are also required for promoting Beige adipocyte biogenesis in response to various environmental stimuli. A better understanding of the molecular mechanisms governing the generation and function of brown and Beige adipocytes is necessary to allow us to control adipose cell fate and stimulate thermogenesis. This may provide a therapeutic approach for the treatment of obesity and obesity-associated diseases, such as type 2 diabetes.
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a synergistic antiobesity effect by a combination of capsinoids and cold temperature through promoting Beige adipocyte biogenesis
Diabetes, 2016Co-Authors: Kana Ohyama, Yoshihito Nogusa, Katsuya Suzuki, Kosaku Shinoda, Makoto Bannai, Shingo KajimuraAbstract:Beige adipocytes emerge postnatally within the white adipose tissue in response to certain environmental cues, such as chronic cold exposure. Because of its highly recruitable nature and relevance to adult humans, Beige adipocytes have gained much attention as an attractive cellular target for antiobesity therapy. However, molecular circuits that preferentially promote Beige adipocyte biogenesis remain poorly understood. We report that a combination of mild cold exposure at 17°C and capsinoids, a nonpungent analog of capsaicin, synergistically and preferentially promotes Beige adipocyte biogenesis and ameliorates diet-induced obesity. Gain- and loss-of-function studies show that the combination of capsinoids and cold exposure synergistically promotes Beige adipocyte development through the β2-adrenoceptor signaling pathway. This synergistic effect on Beige adipocyte biogenesis occurs through an increased half-life of PRDM16, a dominant transcriptional regulator of brown/Beige adipocyte development. We document a previously unappreciated molecular circuit that controls Beige adipocyte biogenesis and suggest a plausible approach to increase whole-body energy expenditure by combining dietary components and environmental cues.
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brown and Beige fat physiological roles beyond heat generation
Cell Metabolism, 2015Co-Authors: Shingo Kajimura, Bruce M. Spiegelman, Patrick SealeAbstract:Since brown adipose tissue (BAT) dissipates energy through UCP1, BAT has garnered attention as a therapeutic intervention for obesity and metabolic diseases including type 2 diabetes. As we better understand the physiological roles of classical brown and Beige adipocytes, it is becoming clear that BAT is not simply a heat-generating organ. Increased Beige fat mass in response to a variety of external/internal cues is associated with significant improvements in glucose and lipid homeostasis that may not be entirely mediated by UCP1. We aim to discuss recent insights regarding the developmental lineages, molecular regulation, and new functions for brown and Beige adipocytes.
Christian Wolfrum - One of the best experts on this subject based on the ideXlab platform.
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ESRRG and PERM1 Govern Mitochondrial Conversion in Brite/Beige Adipocyte Formation.
Frontiers in endocrinology, 2020Co-Authors: Sebastian Müller, Aliki Perdikari, Dianne H. Dapito, Wenfei Sun, Bernd Wollscheid, Miroslav Balaz, Christian WolfrumAbstract:When exposed to cold temperatures, mice increase their thermogenic capacity by an expansion of brown adipose tissue mass and the formation of brite/Beige adipocytes in white adipose tissue depots. However, the process of the transcriptional changes underlying the conversion of a phenotypic white to brite/Beige adipocytes is only poorly understood. By analyzing transcriptome profiles of inguinal adipocytes during cold exposure and in mouse models with a different propensity to form brite/Beige adipocytes, we identified ESRRG and PERM1 as modulators of this process. The production of heat by mitochondrial uncoupled respiration is a key feature of brite/Beige compared to white adipocytes and we show here that both candidates are involved in PGC1α transcriptional network to positively regulate mitochondrial capacity. Moreover, we show that an increased expression of ESRRG or PERM1 supports the formation of brown or brite/Beige adipocytes in vitro and in vivo. These results reveal that ESRRG and PERM1 are early induced in and important regulators of brite/Beige adipocyte formation.
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esrrg and perm1 govern mitochondrial conversion in brite Beige adipocyte formation
Frontiers in Endocrinology, 2020Co-Authors: Sebastian Müller, Aliki Perdikari, Dianne H. Dapito, Wenfei Sun, Bernd Wollscheid, Miroslav Balaz, Christian WolfrumAbstract:When exposed to cold temperatures, mice increase their thermogenic capacity by an expansion of brown adipose tissue mass and the formation of brite/Beige adipocytes in white adipose tissue depots. However, the process of the transcriptional changes underlying the conversion of a phenotypic white to brite/Beige adipocytes is only poorly understood. By analyzing transcriptome profiles of inguinal adipocytes during cold exposure and in mouse models with a different propensity to form brite/Beige adipocytes, we identified ESRRG and PERM1 as modulators of this process. The production of heat by mitochondrial uncoupled respiration is a key feature of brite/Beige compared to white adipocytes and we show here that both candidates are involved in PGC1α transcriptional network to positively regulate mitochondrial capacity. Moreover, we show that an increased expression of ESRRG or PERM1 supports the formation of brown or brite/Beige adipocytes in vitro and in vivo. These results reveal that ESRRG and PERM1 are early induced in and important regulators of brite/Beige adipocyte formation.
Jonathan M. Graff - One of the best experts on this subject based on the ideXlab platform.
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Cellular Aging Contributes to Failure of Cold-Induced Beige Adipocyte Formation in Old Mice and Humans
Cell metabolism, 2016Co-Authors: Daniel C. Berry, Yuwei Jiang, Robert W. Arpke, Elizabeth L. Close, Aki Uchida, David Reading, Eric D. Berglund, Michael Kyba, Jonathan M. GraffAbstract:Cold temperatures induce progenitor cells within white adipose tissue to form Beige adipocytes that burn energy and generate heat; this is a potential anti-diabesity therapy. However, the potential to form cold-induced Beige adipocytes declines with age. This creates a clinical roadblock to potential therapeutic use in older individuals, who constitute a large percentage of the obesity epidemic. Here we show that aging murine and human Beige progenitor cells display a cellular aging, senescence-like phenotype that accounts for their age-dependent failure. Activating the senescence pathway, either genetically or pharmacologically, in young Beige progenitors induces premature cellular senescence and blocks their potential to form cold-induced Beige adipocytes. Conversely, genetically or pharmacologically reversing cellular aging by targeting the p38/MAPK-p16Ink4a pathway in aged mouse or human Beige progenitor cells rejuvenates cold-induced beiging. This in turn increases glucose sensitivity. Collectively, these data indicate that anti-aging or senescence modalities could be a strategy to induce beiging, thereby improving metabolic health in aging humans.
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Mouse strains to study cold-inducible Beige progenitors and Beige adipocyte formation and function
Nature communications, 2016Co-Authors: Daniel C. Berry, Yuwei Jiang, Jonathan M. GraffAbstract:Cold temperatures induce formation of Beige adipocytes, which convert glucose and fatty acids to heat, and may increase energy expenditure, reduce adiposity and lower blood glucose. This therapeutic potential is unrealized, hindered by a dearth of genetic tools to fate map, track and manipulate Beige progenitors and 'beiging'. Here we examined 12 Cre/inducible Cre mouse strains that mark adipocyte, muscle and mural lineages, three proposed Beige origins. Among these mouse strains, only those that marked perivascular mural cells tracked the cold-induced Beige lineage. Two SMA-based strains, SMA-Cre(ERT2) and SMA-rtTA, fate mapped into the majority of cold-induced Beige adipocytes and SMA-marked progenitors appeared essential for beiging. Disruption of the potential of the SMA-tracked progenitors to form Beige adipocytes was accompanied by an inability to maintain body temperature and by hyperglycaemia. Thus, SMA-engineered mice may be useful to track and manipulate Beige progenitors, Beige adipocyte formation and function.
Xiaona Qiao - One of the best experts on this subject based on the ideXlab platform.
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adrenergic independent signaling via chrna2 regulates Beige fat activation
Developmental Cell, 2020Co-Authors: Heejin Jun, Jianke Gong, Xiaona Qiao, Yong Chen, Shanshan Liu, Jine Wang, Alexander J Knights, Margo P EmontAbstract:Summary Maintaining energy homeostasis upon environmental challenges, such as cold or excess calorie intake, is essential to the fitness and survival of mammals. Drug discovery efforts targeting β-adrenergic signaling have not been fruitful after decades of intensive research. We recently identified a new Beige fat regulatory pathway mediated via the nicotinic acetylcholine receptor subunit CHRNA2. Here, we generated fat-specific Chrna2 KO mice and observed thermogenic defects in cold and metabolic dysfunction upon dietary challenges caused by adipocyte-autonomous regulation in vivo. We found that CHRNA2 signaling is activated after acute high fat diet feeding and this effect is manifested through both UCP1- and creatine-mediated mechanisms. Furthermore, our data suggested that CHRNA2 signaling may activate glycolytic Beige fat, a subpopulation of Beige adipocytes mediated by GABPα emerging in the absence of β-adrenergic signaling. These findings reveal the biological significance of the CHRNA2 pathway in Beige fat biogenesis and energy homeostasis.
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an immune Beige adipocyte communication via nicotinic acetylcholine receptor signaling
Nature Medicine, 2018Co-Authors: Hui Yu, Jianke Gong, Juan Jiang, Xiaona Qiao, Eric Perkey, Margo P Emont, Alexander G ZestosAbstract:Beige adipocytes have recently been shown to regulate energy dissipation when activated and help organisms defend against hypothermia and obesity. Prior reports indicate that Beige-like adipocytes exist in adult humans and that they may present novel opportunities to curb the global epidemic in obesity and metabolic illnesses. In an effort to identify unique features of activated Beige adipocytes, we found that expression of the cholinergic receptor nicotinic alpha 2 subunit (Chrna2) was induced in subcutaneous fat during the activation of these cells and that acetylcholine-producing immune cells within this tissue regulated this signaling pathway via paracrine mechanisms. CHRNA2 functioned selectively in uncoupling protein 1 (Ucp1)-positive Beige adipocytes, increasing thermogenesis through a cAMP- and protein kinase A-dependent pathway. Furthermore, this signaling via CHRNA2 was conserved and present in human subcutaneous adipocytes. Inactivation of Chrna2 in mice compromised the cold-induced thermogenic response selectively in subcutaneous fat and exacerbated high-fat diet-induced obesity and associated metabolic disorders, indicating that even partial loss of Beige fat regulation in vivo had detrimental consequences. Our results reveal a Beige-selective immune–adipose interaction mediated through CHRNA2 and identify a novel function of nicotinic acetylcholine receptors in energy metabolism. These findings may lead to identification of therapeutic targets to counteract human obesity. Inhibition of immune cell–derived acetylcholine synthesis or of its signaling via CHRNA2 in Beige adipocytes reduces thermogenesis and exacerbates diet-induced obesity, suggesting a new mode of immuno–fat communication in energy metabolism.
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an immune Beige adipocyte communication via nicotinic acetylcholine receptor signaling
Nature Medicine, 2018Co-Authors: Heejin Jun, Jianke Gong, Juan Jiang, Xiaona Qiao, Eric Perkey, Dongil Kim, Margo P EmontAbstract:Beige adipocytes have recently been shown to regulate energy dissipation when activated and help organisms defend against hypothermia and obesity. Prior reports indicate that Beige-like adipocytes exist in adult humans and that they may present novel opportunities to curb the global epidemic in obesity and metabolic illnesses. In an effort to identify unique features of activated Beige adipocytes, we found that expression of the cholinergic receptor nicotinic alpha 2 subunit (Chrna2) was induced in subcutaneous fat during the activation of these cells and that acetylcholine-producing immune cells within this tissue regulated this signaling pathway via paracrine mechanisms. CHRNA2 functioned selectively in uncoupling protein 1 (Ucp1)-positive Beige adipocytes, increasing thermogenesis through a cAMP- and protein kinase A-dependent pathway. Furthermore, this signaling via CHRNA2 was conserved and present in human subcutaneous adipocytes. Inactivation of Chrna2 in mice compromised the cold-induced thermogenic response selectively in subcutaneous fat and exacerbated high-fat diet-induced obesity and associated metabolic disorders, indicating that even partial loss of Beige fat regulation in vivo had detrimental consequences. Our results reveal a Beige-selective immune-adipose interaction mediated through CHRNA2 and identify a novel function of nicotinic acetylcholine receptors in energy metabolism. These findings may lead to identification of therapeutic targets to counteract human obesity.
Jianke Gong - One of the best experts on this subject based on the ideXlab platform.
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adrenergic independent signaling via chrna2 regulates Beige fat activation
Developmental Cell, 2020Co-Authors: Heejin Jun, Jianke Gong, Xiaona Qiao, Yong Chen, Shanshan Liu, Jine Wang, Alexander J Knights, Margo P EmontAbstract:Summary Maintaining energy homeostasis upon environmental challenges, such as cold or excess calorie intake, is essential to the fitness and survival of mammals. Drug discovery efforts targeting β-adrenergic signaling have not been fruitful after decades of intensive research. We recently identified a new Beige fat regulatory pathway mediated via the nicotinic acetylcholine receptor subunit CHRNA2. Here, we generated fat-specific Chrna2 KO mice and observed thermogenic defects in cold and metabolic dysfunction upon dietary challenges caused by adipocyte-autonomous regulation in vivo. We found that CHRNA2 signaling is activated after acute high fat diet feeding and this effect is manifested through both UCP1- and creatine-mediated mechanisms. Furthermore, our data suggested that CHRNA2 signaling may activate glycolytic Beige fat, a subpopulation of Beige adipocytes mediated by GABPα emerging in the absence of β-adrenergic signaling. These findings reveal the biological significance of the CHRNA2 pathway in Beige fat biogenesis and energy homeostasis.
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an immune Beige adipocyte communication via nicotinic acetylcholine receptor signaling
Nature Medicine, 2018Co-Authors: Hui Yu, Jianke Gong, Juan Jiang, Xiaona Qiao, Eric Perkey, Margo P Emont, Alexander G ZestosAbstract:Beige adipocytes have recently been shown to regulate energy dissipation when activated and help organisms defend against hypothermia and obesity. Prior reports indicate that Beige-like adipocytes exist in adult humans and that they may present novel opportunities to curb the global epidemic in obesity and metabolic illnesses. In an effort to identify unique features of activated Beige adipocytes, we found that expression of the cholinergic receptor nicotinic alpha 2 subunit (Chrna2) was induced in subcutaneous fat during the activation of these cells and that acetylcholine-producing immune cells within this tissue regulated this signaling pathway via paracrine mechanisms. CHRNA2 functioned selectively in uncoupling protein 1 (Ucp1)-positive Beige adipocytes, increasing thermogenesis through a cAMP- and protein kinase A-dependent pathway. Furthermore, this signaling via CHRNA2 was conserved and present in human subcutaneous adipocytes. Inactivation of Chrna2 in mice compromised the cold-induced thermogenic response selectively in subcutaneous fat and exacerbated high-fat diet-induced obesity and associated metabolic disorders, indicating that even partial loss of Beige fat regulation in vivo had detrimental consequences. Our results reveal a Beige-selective immune–adipose interaction mediated through CHRNA2 and identify a novel function of nicotinic acetylcholine receptors in energy metabolism. These findings may lead to identification of therapeutic targets to counteract human obesity. Inhibition of immune cell–derived acetylcholine synthesis or of its signaling via CHRNA2 in Beige adipocytes reduces thermogenesis and exacerbates diet-induced obesity, suggesting a new mode of immuno–fat communication in energy metabolism.
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an immune Beige adipocyte communication via nicotinic acetylcholine receptor signaling
Nature Medicine, 2018Co-Authors: Heejin Jun, Jianke Gong, Juan Jiang, Xiaona Qiao, Eric Perkey, Dongil Kim, Margo P EmontAbstract:Beige adipocytes have recently been shown to regulate energy dissipation when activated and help organisms defend against hypothermia and obesity. Prior reports indicate that Beige-like adipocytes exist in adult humans and that they may present novel opportunities to curb the global epidemic in obesity and metabolic illnesses. In an effort to identify unique features of activated Beige adipocytes, we found that expression of the cholinergic receptor nicotinic alpha 2 subunit (Chrna2) was induced in subcutaneous fat during the activation of these cells and that acetylcholine-producing immune cells within this tissue regulated this signaling pathway via paracrine mechanisms. CHRNA2 functioned selectively in uncoupling protein 1 (Ucp1)-positive Beige adipocytes, increasing thermogenesis through a cAMP- and protein kinase A-dependent pathway. Furthermore, this signaling via CHRNA2 was conserved and present in human subcutaneous adipocytes. Inactivation of Chrna2 in mice compromised the cold-induced thermogenic response selectively in subcutaneous fat and exacerbated high-fat diet-induced obesity and associated metabolic disorders, indicating that even partial loss of Beige fat regulation in vivo had detrimental consequences. Our results reveal a Beige-selective immune-adipose interaction mediated through CHRNA2 and identify a novel function of nicotinic acetylcholine receptors in energy metabolism. These findings may lead to identification of therapeutic targets to counteract human obesity.