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Adenosine activates brown adipose tissue and recruits beige adipocytes via A_(2A) receptors

机译:腺苷通过A_(2A)受体激活棕色脂肪组织并募集米色脂肪细胞

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摘要

Brown adipose tissue (BAT) is specialized in energy expenditure, making it a potential target for anti-obesity therapies. Following exposure to cold, BAT is activated by the sympathetic nervous system with concomitant release of catecholamines and activation of β-adrenergic receptors. Because BAT therapies based on cold exposure or β-adrenergic agonists are clinically not feasible, alternative strategies must be explored. Purinergic co-transmission might be involved in sympathetic control of BAT and previous studies reported inhibitory effects of the purinergic transmitter adenosine in BAT from hamster or rat. However, the role of adenosine in human BAT is unknown. Here we show that adenosine activates human and murine brown adipocytes at low nanomolar concentrations. Adenosine is released in BAT during stimulation of sympathetic nerves as well as from brown adipocytes. The adenosine A_(2A) receptor is the most abundant adenosine receptor in human and murine BAT. Pharmacological blockade or genetic loss of A_(2A) receptors in mice causes a decrease in BAT-dependent thermo-genesis, whereas treatment with A_(2A) agonists significantly increases energy expenditure. Moreover, pharmacological stimulation of A_(2A) receptors or injection of lentiviral vectors expressing the A_(2A) receptor into white fat induces brown-like cells-so-called beige adipocytes. Importantly, mice fed a high-fat diet and treated with an A_(2A) agonist are leaner with improved glucose tolerance. Taken together, our results demonstrate that adenosine- A_(2A) signalling plays an unexpected physiological role in sympathetic BAT activation and protects mice from diet-induced obesity. Those findings reveal new possibilities for developing novel obesity therapies.
机译:棕色脂肪组织(BAT)专门用于能量消耗,使其成为抗肥胖疗法的潜在目标。暴露于寒冷后,BAT被交感神经系统激活,并伴随儿茶酚胺释放和β-肾上腺素受体激活。由于基于冷暴露或β-肾上腺素激动剂的BAT治疗在临床上不可行,因此必须探索替代策略。嘌呤能共传递可能参与BAT的交感神经控制,以前的研究报道嘌呤能传递腺苷对仓鼠或大鼠的BAT具有抑制作用。但是,腺苷在人BAT中的作用尚不清楚。在这里,我们显示腺苷在低纳摩尔浓度下激活人和鼠类棕色脂肪细胞。腺苷在刺激交感神经期间以及从棕色脂肪细胞中释放到BAT中。腺苷A_(2A)受体是人和鼠BAT中最丰富的腺苷受体。小鼠的A_(2A)受体在药理学上的封锁或遗传损失导致BAT依赖的热生成减少,而A_(2A)激动剂的治疗显着增加了能量消耗。此外,药理刺激A_(2A)受体或将表达A_(2A)受体的慢病毒载体注射入白色脂肪中,会诱发褐色样细胞,即所谓的米色脂肪细胞。重要的是,喂食高脂饮食并用A_(2A)激动剂治疗的小鼠更苗条,并且葡萄糖耐量得到改善。两者合计,我们的结果表明,腺苷A_(2A)信号转导BAT活化中起意想不到的生理作用,并保护小鼠免受饮食诱发的肥胖。这些发现揭示了开发新型肥胖疗法的新可能性。

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  • 来源
    《Nature》 |2014年第7531期|395-399|共5页
  • 作者单位

    Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany;

    Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany,Research Training Group 1873, University of Bonn, 53127 Bonn, Germany;

    Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany;

    The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, 2100 Copenhagen, Denmark;

    Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany;

    Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany;

    Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany;

    Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany,Research Training Group 1873, University of Bonn, 53127 Bonn, Germany;

    Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany;

    Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany;

    Pharmaceutical Institute, Pharmaceutical Chemistry Ⅰ, University of Bonn, 53121 Bonn, Germany;

    Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, 04318 Leipzig, Germany;

    Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, 04318 Leipzig, Germany;

    Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, 04318 Leipzig, Germany;

    Department of Medical and Clinical Genetics, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, 413 90 Gothenburg, Sweden;

    Department of Medical and Clinical Genetics, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, 413 90 Gothenburg, Sweden;

    Department of Medical and Clinical Genetics, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, 413 90 Gothenburg, Sweden;

    Department for Molecular Cardiology, University of Duessetdorf, 40225 Duesseldorf, Germany;

    Medicity Research Laboratory, University of Turku, 20520 Turku, Finland;

    Pharmaceutical Institute, Pharmaceutical Chemistry Ⅰ, University of Bonn, 53121 Bonn, Germany,Pharma Center, University of Bonn, 53127 Bonn, Germany;

    Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany,Pharma Center, University of Bonn, 53127 Bonn, Germany;

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