Lactate fluxes mediated by the monocarboxylate transporter-1 are key determinants of the metabolic activity of beige adipocytes.
Lactate fluxes mediated by the monocarboxylate transporter-1 are key determinants of the metabolic activity of beige adipocytes.
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DOI：
10.1074/jbc.ra120.016303
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Carrière A
中科院分区：
文献类型：
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作者：
Lagarde D;Jeanson Y;Barreau C;Moro C;Peyriga L;Cahoreau E;Guissard C;Arnaud E;Galinier A;Bouzier-Sore AK;Pellerin L;Chouchani ET;Pénicaud L;Ader I;Portais JC;Casteilla L;Carrière A
能量耗散的棕色/米色脂肪细胞的激活代表了一种针对代谢紊乱的有吸引力的治疗策略。虽然已知乳酸通过调节 Ucp1 基因表达来诱导米色，但乳酸转运蛋白对米色脂肪细胞持续代谢活动的作用仍知之甚少。为了探索乳酸转运单羧酸转运蛋白（MCT）的功能，我们结合了原代细胞培养研究、13C同位素示踪、激光显微切割实验和小鼠脂肪垫的原位免疫荧光。解剖白色脂肪组织异质性表明，MCT1 在可诱导米色脂肪细胞中表达，因为冷暴露后解偶联蛋白 1 的出现仅限于表达 MCT1 的脂肪细胞亚群，表明 MCT1 作为可诱导米色脂肪细胞的标志物。我们还观察到 MCT1 介导双向且同时向内和向外的乳酸通量，这是由经典 β3-肾上腺素信号通路激活的米色脂肪细胞有效利用葡萄糖所必需的。最后，我们证明，即使在葡萄糖不受限制的情况下，也会通过 MCT1 导入大量乳酸，从而促进米色脂肪细胞的氧化代谢。这些数据强调了乳酸通量在根据细胞外代谢条件微调米色脂肪细胞的代谢活动中的关键作用，并强化了乳酸代谢在控制能量稳态中的新兴作用。
Activation of energy-dissipating brown/beige adipocytes represents an attractive therapeutic strategy against metabolic disorders. While lactate is known to induce beiging through the regulation of Ucp1 gene expression, the role of lactate transporters on beige adipocytes' ongoing metabolic activity remains poorly understood. To explore the function of the lactate-transporting monocarboxylate transporters (MCTs), we used a combination of primary cell culture studies, 13C isotopic tracing, laser microdissection experiments, and in situ immunofluorescence of murine adipose fat pads. Dissecting white adipose tissue heterogeneity revealed that the MCT1 is expressed in inducible beige adipocytes as the emergence of uncoupling protein 1 after cold exposure was restricted to a subpopulation of MCT1-expressing adipocytes suggesting MCT1 as a marker of inducible beige adipocytes. We also observed that MCT1 mediates bidirectional and simultaneous inward and outward lactate fluxes, which were required for efficient utilization of glucose by beige adipocytes activated by the canonical β3-adrenergic signaling pathway. Finally, we demonstrated that significant lactate import through MCT1 occurs even when glucose is not limiting, which feeds the oxidative metabolism of beige adipocytes. These data highlight the key role of lactate fluxes in finely tuning the metabolic activity of beige adipocytes according to extracellular metabolic conditions and reinforce the emerging role of lactate metabolism in the control of energy homeostasis.