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凋亡的棕色脂肪细胞通过细胞外肌苷增强能量消耗
2022-07-06 14:13
来源：小柯机器人

德国波恩大学Alexander Pfeifer、Birte Niemann等研究人员合作发现，凋亡的棕色脂肪细胞通过细胞外肌苷增强能量消耗。相关论文于2022年7月5日在线发表于国际学术期刊《自然》。

通过非靶向代谢组学，研究人员证明，凋亡的棕色脂肪组织（BAT）会释放一种特定的代谢物模式，其中嘌呤代谢物高度富集。有趣的是，这种凋亡的分泌物组增强了健康脂肪细胞中生热程序的表达。这种作用是由嘌呤肌苷介导的，它通过cAMP/蛋白激酶A信号通路刺激棕色脂肪细胞的能量消耗（EE）。用肌苷治疗小鼠增加了BAT依赖的EE，并诱发了白色脂肪组织的"褐色化"。
 
从机制上讲，平衡核苷转运体1（ENT1，SLC29A1）调节BAT中的肌苷水平：ENT1缺陷会增加细胞外肌苷水平，从而增强致热脂肪细胞的分化。在小鼠中，ENT1的药物抑制以及全局性和脂肪特异性敲除分别增强了BAT的活性并抵消了饮食引起的肥胖。在人类棕色脂肪细胞中，ENT1的敲除或阻断增加了细胞外肌苷，从而增强了产热能力。相反，高ENT1水平与人类脂肪组织中生热标志物UCP1的低表达相关联。最后，人类ENT1的Ile216Thr功能丧失突变与BMI明显降低有关，携带Thr变体的个体肥胖几率降低59%。这些数据表明，肌苷是一种在细胞凋亡过程中释放的代谢物，具有"取代我"的信号功能，可以调节生热脂肪并对抗肥胖。
 
据悉，BAT消耗能量并促进心肺代谢健康。肥胖和衰老过程中BAT的丧失是以BAT为中心的肥胖治疗的主要障碍，但对BAT的凋亡了解不多。
 
附：英文原文
 
Title: Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine

Author: Niemann, Birte, Haufs-Brusberg, Saskia, Puetz, Laura, Feickert, Martin, Jaeckstein, Michelle Y., Hoffmann, Anne, Zurkovic, Jelena, Heine, Markus, Trautmann, Eva-Maria, Mller, Christa E., Tnjes, Anke, Schlein, Christian, Jafari, Azin, Eltzschig, Holger K., Gnad, Thorsten, Blher, Matthias, Krahmer, Natalie, Kovacs, Peter, Heeren, Joerg, Pfeifer, Alexander

Issue&Volume: 2022-07-05

Abstract: Brown adipose tissue (BAT) dissipates energy1,2 and promotes cardio-metabolic health3. Loss of BAT during obesity and aging is a principal hurdle for BAT-centered obesity therapies, but not much is known about BAT apoptosis. Here, untargeted metabolomics demonstrated that apoptotic brown adipocytes release a specific pattern of metabolites with purine metabolites being highly enriched. Interestingly, this apoptotic secretome enhances expression of the thermogenic program in healthy adipocytes. This effect is mediated by the purine inosine which stimulates energy expenditure (EE) in brown adipocytes via the cAMP/protein kinase A signaling pathway. Treatment of mice with inosine increased BAT-dependent EE and induced “browning” of white adipose tissue. Mechanistically, the equilibrative nucleoside transporter 1 (ENT1, SLC29A1) regulates inosine levels in BAT: ENT1-deficiency increases extracellular inosine levels and consequently enhances thermogenic adipocyte differentiation. In mice, pharmacological inhibition of ENT1 as well as global and adipose-specific ablation enhanced BAT activity and counteracted diet-induced obesity, respectively. In human brown adipocytes, knockdown or blockade of ENT1 increased extracellular inosine, which enhanced thermogenic capacity. Conversely, high ENT1 levels correlated with lower expression of the thermogenic marker UCP1 in human adipose tissues. Finally, the Ile216Thr loss of function mutation in human ENT1 was associated with significantly lower BMI and 59% lower odds of obesity for individuals carrying the Thr variant. Our data identify inosine as a metabolite released during apoptosis with “replace me” signaling function that regulates thermogenic fat and counteracts obesity.

DOI: 10.1038/s41586-022-05041-0

Source: https://www.nature.com/articles/s41586-022-05041-0

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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