Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine.
Apoptotic brown adipocytes enhance energy expenditure via extracellular inosine.
复制标题
凋亡的棕色脂肪细胞通过细胞外肌苷增加能量消耗。
DOI：
10.1038/s41586-022-05041-0
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发表时间：
2022-09
期刊：
影响因子：
64.8
通讯作者：
Pfeifer, Alexander
中科院分区：
文献类型：
--
作者：
Niemann, Birte;Haufs-Brusberg, Saskia;Puetz, Laura;Feickert, Martin;Jaeckstein, Michelle Y.;Hoffmann, Anne;Zurkovic, Jelena;Heine, Markus;Trautmann, Eva-Maria;Mueller, Christa E.;Toenjes, Anke;Schlein, Christian;Jafari, Azin;Eltzschig, Holger K.;Gnad, Thorsten;Bluher, Matthias;Krahmer, Natalie;Kovacs, Peter;Heeren, Joerg;Pfeifer, Alexander
棕色脂肪组织（BAT）消耗能量，促进心脏代谢健康。在肥胖和衰老过程中BAT的丢失是以BAT为中心的肥胖治疗的主要障碍，但对BAT细胞凋亡知之甚少。在这里，非靶向代谢组学表明，凋亡的棕色脂肪细胞释放特定模式的代谢产物，嘌呤代谢产物高度富集。这种凋亡分泌蛋白组增强了健康脂肪细胞中产热程序的表达。这种作用是由嘌呤肌苷介导的，嘌呤肌苷通过环腺苷一磷酸-蛋白激酶A信号通路刺激棕色脂肪细胞的能量消耗。用肌苷处理小鼠增加BAT依赖性能量消耗，并诱导白色脂肪组织的“布朗宁”。从机制上讲，平衡型核苷转运蛋白1（ENT 1，SLC 29 A1）调节BAT中的肌苷水平：ENT 1缺乏增加细胞外肌苷水平，从而增强产热脂肪细胞分化。在小鼠中，ENT 1的药理学抑制以及整体和脂肪特异性消融分别增强了BAT活性并抵消了饮食诱导的肥胖。在人类褐色脂肪细胞中，敲低或阻断ENT 1增加细胞外肌苷，从而增强产热能力。相反，高ENT 1水平与人脂肪组织中产热标志物UCP 1的低表达相关。最后，人类ENT 1中Ile 216 Thr功能缺失突变与携带Thr变体的个体的体重指数显著降低和肥胖几率降低59%相关。我们的数据确定肌苷作为细胞凋亡过程中释放的代谢产物，具有调节产热脂肪和抵消肥胖的“取代我”信号功能。非靶向代谢组学表明，凋亡的棕色脂肪细胞释放特定模式的代谢产物，其中嘌呤代谢产物高度富集，并且肌苷被鉴定为在凋亡期间释放的代谢产物，其调节产热脂肪并对抗肥胖。
Brown adipose tissue (BAT) dissipates energy and promotes cardiometabolic health. Loss of BAT during obesity and ageing is a principal hurdle for BAT-centred 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. This apoptotic secretome enhances expression of the thermogenic programme in healthy adipocytes. This effect is mediated by the purine inosine that stimulates energy expenditure in brown adipocytes by the cyclic adenosine monophosphate–protein kinase A signalling pathway. Treatment of mice with inosine increased BAT-dependent energy expenditure 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 body mass index and 59% lower odds of obesity for individuals carrying the Thr variant. Our data identify inosine as a metabolite released during apoptosis with a ‘replace me’ signalling function that regulates thermogenic fat and counteracts obesity. Untargeted metabolomics demonstrate that apoptotic brown adipocytes release a specific pattern of metabolites with purine metabolites being highly enriched, and inosine is identified as a metabolite released during apoptosis regulating thermogenic fat and counteracting obesity.
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影响因子：
82.9
作者：
Fischer K;Ruiz HH;Jhun K;Finan B;Oberlin DJ;van der Heide V;Kalinovich AV;Petrovic N;Wolf Y;Clemmensen C;Shin AC;Divanovic S;Brombacher F;Glasmacher E;Keipert S;Jastroch M;Nagler J;Schramm KW;Medrikova D;Collden G;Woods SC;Herzig S;Homann D;Jung S;Nedergaard J;Cannon B;Tschöp MH;Müller TD;Buettner C
通讯作者：
Buettner C
影响因子：
29
作者：
Kajimura S;Spiegelman BM;Seale P
通讯作者：
Seale P
影响因子：
29
作者：
Fischer, Alexander W.;Jaeckstein, Michelle Y.;Heeren, Joerg
通讯作者：
Heeren, Joerg
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1007/164_2018_151
发表时间：
2019-01-01
期刊：
BROWN ADIPOSE TISSUE
影响因子：
--
作者：
Graja, Antonia;Gohlke, Sabrina;Schulz, Tim J.
通讯作者：
Schulz, Tim J.