Accumulation of succinate controls activation of adipose tissue thermogenesis.
Accumulation of succinate controls activation of adipose tissue thermogenesis.
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DOI：
10.1038/s41586-018-0353-2
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发表时间：
2018-08
期刊：
影响因子：
64.8
通讯作者：
Chouchani ET
中科院分区：
文献类型：
--
作者：
Mills EL;Pierce KA;Jedrychowski MP;Garrity R;Winther S;Vidoni S;Yoneshiro T;Spinelli JB;Lu GZ;Kazak L;Banks AS;Haigis MC;Kajimura S;Murphy MP;Gygi SP;Clish CB;Chouchani ET
棕色和米色脂肪组织产热可以对抗代谢疾病，这需要外部刺激的激活。脂肪细胞脂解通过cAMP/PKA信号启动产热呼吸，这一途径已经受到长期的临床研究。在这里，我们应用比较代谢组学方法，并确定了一个独立的代谢途径，控制体内脂肪组织产热的急性激活。我们表明，大量和选择性积累的三羧酸（TCA）循环中间琥珀酸盐是热源脂肪组织在暴露于寒冷激活后的代谢特征。琥珀酸积累独立于肾上腺素能级联发生，足以提高体内棕色脂肪细胞的产热呼吸。这种选择性积累可以由棕色脂肪细胞隔离升高的循环琥珀酸盐的新能力驱动，此外，棕色脂肪组织（BAT）依赖的产热可以通过小鼠全身给药琥珀酸盐启动。从细胞外环境中积累的琥珀酸盐被棕色脂肪细胞线粒体迅速吸收，琥珀酸脱氢酶（SDH）对其氧化是激活产热所必需的。在机制上，我们发现SDH介导的琥珀酸氧化启动活性氧（ROS）的产生，从而驱动解偶联蛋白1 （UCP1）依赖的产热呼吸，而SDH抑制产热。最后，我们发现这一途径可以通过循环琥珀酸盐的药理学升高来激活，从而驱动体内ucp1依赖的BAT产热，从而刺激对饮食诱导的肥胖的强大保护并提高葡萄糖耐量。这些发现揭示了一种意想不到的机制来控制体内产热，利用琥珀酸盐作为一种系统衍生的产热分子。
Brown and beige adipose tissue thermogenesis can combat metabolic disease, which requires activation by extrinsic stimuli. Adipocyte lipolysis through cAMP/PKA signaling initiates thermogenic respiration, and this pathway has been subject to longstanding clinical investigation. Here we apply a comparative metabolomic approach and identify an independent metabolic pathway that controls acute activation of adipose tissue thermogenesis in vivo. We show that substantial and selective accumulation of the tricarboxylic acid (TCA) cycle intermediate succinate is a metabolic signature of thermogenic adipose tissue upon activation by exposure to cold. Succinate accumulation occurs independently of the adrenergic cascade and is sufficient to elevate brown adipocyte thermogenic respiration in vivo. This selective accumulation can be driven by a newfound capacity for brown adipocytes to sequester elevated circulating succinate, furthermore, brown adipose tissue (BAT)-dependent thermogenesis can be initiated by systemic administration of succinate in mice. Succinate that is accumulated from the extracellular milieu is rapidly taken up by brown adipocyte mitochondria, and its oxidation by succinate dehydrogenase (SDH) is required for its activation of thermogenesis. Mechanistically, we find that SDH mediated-succinate oxidation initiates reactive oxygen species (ROS) production and thereby drives uncoupling protein 1 (UCP1)-dependent thermogenic respiration, while SDH inhibition supresses thermogenesis. Finally, we show that this pathway can be activated by pharmacological elevation of circulating succinate to drive UCP1-dependent BAT thermogenesis in vivo, which stimulates robust protection against diet-induced obesity and improves glucose tolerance. These findings reveal an unexpected mechanism for control of thermogenesis in vivo, utilizing succinate as a systemically-derived thermogenic molecule.
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DOI：
10.1042/bj20081386
发表时间：
2009-01-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Murphy MP
通讯作者：
Murphy MP
影响因子：
64.5
作者：
Huttlin EL;Jedrychowski MP;Elias JE;Goswami T;Rad R;Beausoleil SA;Villén J;Haas W;Sowa ME;Gygi SP
通讯作者：
Gygi SP
影响因子：
64.5
作者：
Faubert B;Li KY;Cai L;Hensley CT;Kim J;Zacharias LG;Yang C;Do QN;Doucette S;Burguete D;Li H;Huet G;Yuan Q;Wigal T;Butt Y;Ni M;Torrealba J;Oliver D;Lenkinski RE;Malloy CR;Wachsmann JW;Young JD;Kernstine K;DeBerardinis RJ
通讯作者：
DeBerardinis RJ
影响因子：
16.6
作者：
Ehinger JK;Piel S;Ford R;Karlsson M;Sjövall F;Frostner EÅ;Morota S;Taylor RW;Turnbull DM;Cornell C;Moss SJ;Metzsch C;Hansson MJ;Fliri H;Elmér E
通讯作者：
Elmér E
影响因子：
8.2
作者：
Carey, A. L.;Formosa, M. F.;Kingwell, B. A.
通讯作者：
Kingwell, B. A.